Bicyclic heteroaryl inhibitors of pde4

ABSTRACT

The present invention relates to compounds and methods which may be useful as inhibitors of phosphodiesterase 4 (PDE4) for the treatment or prevention of inflammatory diseases and other diseases involving elevated levels of cytokines and proinflammatory mediators.

This application claims the benefit of U.S. Provisional Applications No.60/819,509, filed Jul. 7, 2006, and No. 60/886,825, filed Jan. 26, 2007,the disclosures of which are hereby incorporated by reference as ifwritten herein in their entireties.

Disclosed herein are potent and selective new bicyclic heteroarylcompounds, certain of which have been found to be useful as inhibitorsof phosphodiesterase 4 (PDE4), compositions comprising the same, andtheir application as pharmaceuticals for the treatment of disease.Methods of inhibition of PDE4 activity are also provided, as well asmethods for the treatment of inflammatory diseases and other diseasesinvolving elevated levels of cytokines and proinflammatory mediators.

Chronic inflammation is a multi-factorial disease complicationcharacterized by activation of multiple types of inflammatory cells, forexample cells of lymphoid lineage (including T lymphocytes) and myeloidlineage (including granulocytes, macrophages, and monocytes).Proinflammatory mediators, including cytokines, such as tumor necrosisfactor (TNF) and interleukin-1 (IL-1), are produced by these activatedcells. Accordingly, an agent that suppresses the activation of thesecells, or their production of proinflammatory cytokines, would be usefulin the therapeutic treatment of inflammatory diseases and other diseasesinvolving elevated levels of cytokines.

Cyclic adenosine monophosphate (cAMP) is a second messenger thatmediates the biologic responses of cells to a wide range ofextracellular stimuli. When the appropriate agonist binds to specificcell surface receptors, adenylate cyclase is activated to convertadenosine triphosphate (ATP) to cAMP. It is theorized that the agonistinduced actions of cAMP within the cell are mediated predominately bythe action of cAMP-dependent protein kinases. The intracellular actionsof cAMP are terminated by either a transport of the nucleotide to theoutside of the cell, or by enzymatic cleavage by cyclic nucleotidephosphodiesterases (PDEs), which hydrolyze the 3′-phosphodiester bond toform 5′-adenosine monophosphate (5′-AMP). 5′-AMP is an inactivemetabolite.

The superfamily of PDEs is subdivided into two major classes, class Iand class II, which have no recognizable sequence similarity. Class Iincludes all known mammalian PDEs and is comprised of 11 identifiedfamilies that are products of separate genes. Some PDEs are highlyspecific for hydrolysis of cAMP (PDE4, PDE7, PDE8), some are highlycGMP-specific (PDE5, PDE6, PDE9), and some have mixed specificity (PDE1,PDE2, PDE3, PDE10, PDE11). All of the characterized mammalian PDEs aredimeric, but the importance of the dimeric structure for function ineach of the PDEs is unknown.

The PDE4 subfamily is comprised of 4 members: PDE4A, PDE4B, PDE4C, andPDE4D. These enzymes possess N-terminal regulatory domains thatpresumably mediate dimerization, which results in optimally regulatedPDE activity. In addition, activity is regulated via cAMP-dependentprotein kinase phosphorylation sites in this upstream regulatory domain.PDE4 enzymes are broadly expressed and distributed.

Elevated levels of cAMP in human myeloid and lymphoid lineage cells areassociated with the suppression of cell activation. The intracellularenzyme family of PDEs, therefore, regulates the level of cAMP in cells.PDE4 is a predominant PDE isotype in these cells, and is a majorcontributor to cAMP degradation. Accordingly, the inhibition of PDEfunction would prevent the conversion of cAMP to the inactive metabolite5′-AMP and, consequently, maintain higher cAMP levels, and, accordingly,suppress cell activation.

PDE4 inhibitors have been shown to inhibit production of TNFα andpartially inhibit IL-1β release by monocytes (see Semmler et al., Int.J. Immunopharmacol., 15, pp. 409-413, (1993); Molnar-Kimber et al.,Mediators of Inflammation, 1, pp. 411-417, (1992)). PDE4 inhibitors alsohave been shown to inhibit the production of superoxide radicals fromhuman polymorphonuclear leukocytes (see Verghese et al., J. Mol. Cell.Cardiol., 21 (Suppl. 2), S61 (1989); Nielson et al., J. AllergyImmunol., 86, pp. 801-808, (1990)); to inhibit the release of vasoactiveamines and prostanoids from human basophils (see Peachell et al., J.Immunol., 148, pp. 2503-2510, (1992)); to inhibit respiratory bursts ineosinophils (see Dent et al., J. Pharmacol., 103, pp. 1339-1346,(1991)); and to inhibit the activation of human T-lymphocytes (seeRobicsek et al., Biochem. Pharmacol., 42, pp. 869-877, (1991)).

Inflammatory cell activation and excessive or unregulated cytokine(e.g., TNFα and IL-1β production are implicated in allergic, autoimmune,and inflammatory diseases and disorders, such as rheumatoid arthritis,osteoarthritis, gouty arthritis, spondylitis, thyroid associatedophthalmopathy, Behcet's disease, sepsis, septic shock, endotoxic shock,gram negative sepsis, gram positive sepsis, toxic shock syndrome,asthma, chronic bronchitis, adult respiratory distress syndrome, chronicpulmonary inflammatory disease, such as chronic obstructive pulmonarydisease, silicosis, pulmonary sarcoidosis, reperfusion injury of themyocardium, brain, and extremities, fibrosis, cystic fibrosis, keloidformation, scar formation, atherosclerosis, transplant rejectiondisorders, such as graft vs. host reaction and allograft rejection,chronic glomerulonephritis, lupus, inflammatory bowel disease, such asCrohn's disease and ulcerative colitis, proliferative lymphocytediseases, such as leukemia, ophthalmologic diseases such as dry eye andocular pain resulting from inflammation or surgery, and inflammatorydermatoses, such as atopic dermatitis, psoriasis, and urticaria.

Other conditions characterized by elevated cytokine levels include braininjury due to moderate trauma, cardiomyopathies, such as congestiveheart failure, cachexia, cachexia secondary to infection or malignancy,cachexia secondary to acquired immune deficiency syndrome (AIDS), ARC(AIDS related complex), fever myalgias due to infection, cerebralmalaria, osteoporosis and bone resorption diseases, keloid formation,scar tissue formation, and pyrexia.

Additionally, several properties of TNFα, such as stimulation ofcollagenases, stimulation of angiogenesis in vivo, stimulation of boneresorption, and an ability to increase the adherence of tumor cells toendothelium, are consistent with a role for TNF in the development andmetastatic spread of cancer in the host. TNFα recently has been directlyimplicated in the promotion of growth and metastasis of tumor cells (seeOrosz et al., J. Exp. Med., 177, pp. 1391-1398, (1993)).

Investigators have shown considerable interest in the use of PDE4inhibitors as anti-inflammatory agents. Early evidence indicates thatPDE4 inhibition has beneficial effects on a variety of inflammatorycells such as monocytes, macrophages, T-cells of the Th-1 lineage, andgranulocytes. The synthesis and/or release of many proinflammatorymediators, such as cytokines, lipid mediators, superoxide, and biogenicamines, such as histamine, have been attenuated in these cells by theaction of PDE4 inhibitors. The PDE4 inhibitors also affect othercellular functions including T-cell proliferation, granulocytetransmigration in response to chemotoxic substances, and integrity ofendothelial cell junctions within the vasculature.

The design, synthesis, and screening of various PDE4 inhibitors havebeen reported. Methylxanthines, such as caffeine and theophylline, werethe first PDE inhibitors discovered, but these compounds arenonselective with respect to which PDE is inhibited. The drug rolipram,an antidepressant agent, was one of the first reported specific PDE4inhibitors, with a reported IC₅₀ of about 200 nM with respect toinhibiting recombinant human PDE4.

Investigators have continued to search for PDE4 inhibitors that are moreselective with respect to inhibiting PDE4, that have a lower IC₅₀ thanrolipram, and that avoid the undesirable central nervous system (CNS)side effects, such as retching, vomiting, and sedation, associated withthe administration of rolipram. In addition, several companies are nowundertaking clinical trials of other PDE4 inhibitors. However, problemsrelating to efficacy and adverse side effects, such as emesis andcentral nervous system disturbances, remain unsolved.

Accordingly, compounds that selectively inhibit PDE4, and that reduce oreliminate the adverse side effects associated with prior PDE4inhibitors, would be useful in the treatment of allergic andinflammatory diseases, and other diseases associated with excessive orunregulated production of cytokines, such as TNF. In addition, selectivePDE4 inhibitors would be useful in the treatment of diseases that areassociated with elevated cAMP levels or PDE4 function in a particulartarget tissue.

Novel compounds and pharmaceutical compositions useful asanti-inflammatory agents via the inhibition of PDE4 have been found,together with methods of synthesizing and using the compounds includingmethods for inhibiting PDE4 in a patient by administering the compounds.

Disclosed herein is a class of compounds, certain of which have beenfound to be useful in treating PDE4-mediated disorders and conditions,defined by structural Formula I:

wherein:

A is an optionally substituted saturated or unsaturated hydrocarbonchain or a heteroatom-comprising hydrocarbon chain having from 3 to 5atoms, forming a five- to seven-membered ring;

U, and V are independently selected from the group consisting of O,N(R⁷) and SO_(q);

R¹ and R² are independently selected from the group consisting ofhydrogen, —(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl,alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted;

s is 0-8;

G¹ is selected from the group consisting of alkoxy, amino, amido,carbonyl, hydroxy, ether, an amino acid, and null;

G² is selected from the group consisting of alkyl, alkoxy, amino, aryl,halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino,guanidine, an amino acid, and null, any of which may be optionallysubstituted;

G³ is selected from the group consisting of alkyl, alkoxy, amino,hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted;

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, halogen, alkoxy and lower alkyl;

R⁵ is selected from the group consisting of —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)—and —(CR¹²R¹³)_(p)—;

m, n, and q are each independently 0, 1 or 2;

p is 1 or 2;

W is selected from the group consisting of O, N(R⁷), C(O)N(R⁷), andSO_(q);

R⁶ is selected from the group consisting of carboxy, alkylcarboxy,amido, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,heteroalkyl, acyl, and hydroxamic acid, any of which may be optionallysubstituted;

R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ are each independently selected fromthe group consisting of hydrogen, halogen, hydroxyl, lower alkyl,hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl, andaminoalkoxy; and hydrogen and optionally substituted lower alkyl.

Certain compounds according to the present invention possess useful PDE4inhibiting or modulating activity, and may be used in the treatment orprophylaxis of a disease or condition in which PDE4 plays an activerole. Thus, in broad aspect, the certain embodiments of the presentinvention also provide pharmaceutical compositions comprising one ormore compounds disclosed herein together with a pharmaceuticallyacceptable carrier, as well as methods of making and using the compoundsand compositions. Certain embodiments of the present invention providemethods for inhibiting PDE4. Other embodiments of the present inventionprovide methods for treating a PDE4-mediated disorder in a patient inneed of such treatment, comprising administering to said patient atherapeutically effective amount of a compound or composition accordingto the present invention. Related embodiments disclose the use ofcertain compounds disclosed herein as therapeutic agents, for example,in treating inflammatory diseases and other diseases involving elevatedlevels of cytokines and proinflammatory mediators. The present inventionalso contemplates the use of certain compounds disclosed herein for usein the manufacture of a medicament for the treatment of a disease orcondition ameliorated by the inhibition of PDE4.

In further embodiments, compounds of the present invention havestructural formula II

wherein:

X¹ is NR¹⁴;

X² is selected from the group consisting of C(O), (CR¹⁵R¹⁶) and null;

X³ is selected from the group consisting of C(O), N(R¹⁷) and (CR¹⁸R¹⁹);

R¹ and R² are independently selected from the group consisting ofhydrogen, —(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl,alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted;

s is 0-8;

G¹ is selected from the group consisting of alkoxy, amino, amido,carbonyl, hydroxy, ether, an amino acid, and null;

G² is selected from the group consisting of alkyl, alkoxy, amino, aryl,halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino,guanidine, an amino acid, and null, any of which may be optionallysubstituted;

G³ is selected from the group consisting of alkyl, alkoxy, amino,hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, halogen, alkoxy and lower alkyl;

R⁵ is selected from the group consisting of —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)—and —(CR¹²R¹³)_(p)—;

m, n, and q are each independently 0, 1 or 2;

p is 1 or 2;

W is selected from the group consisting of O, N(R⁷), C(O)N(R⁷), andSO_(q);

R⁶ is selected from the group consisting of carboxy, alkylcarboxy,amido, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,heteroalkyl, acyl, and hydroxamic acid, any of which may be optionallysubstituted;

R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from thegroup consisting of hydrogen and optionally substituted lower alkyl;

R¹⁴ and R¹⁷ are each independently selected from the group consisting ofhydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl, haloalkyl,aminoalkyl, and a bond; and

R¹⁵, R¹⁶, R¹⁸ and R¹⁹ are each independently selected from the groupconsisting of hydrogen, halogen, lower alkyl, haloalkyl, alkoxy,haloalkoxy, amino, aminoalkyl, aminoalkoxy and a bond.

In further embodiments, compounds of the present invention havestructural formula III

wherein:

X¹ is NR¹⁴;

X² is selected from the group consisting of C(O) and null;

X³ is selected from the group consisting of C(O) and (CR¹⁸R¹⁹);

R¹ and R² are independently selected from the group consisting ofhydrogen, —(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl,alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl,alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted;

s is 1-8;

G¹ is selected from the group consisting of alkoxy, amino, amido,carbonyl, hydroxy, ether, an amino acid, and null;

G² is selected from the group consisting of alkyl, alkoxy, amino, aryl,halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino,guanidine, an amino acid, and null, any of which may be optionallysubstituted;

G³ is selected from the group consisting of alkyl, alkoxy, amino,hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, halogen, alkoxy and lower alkyl;

R⁵ is selected from the group consisting of —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)—and —(CR¹²R¹³)_(p)—;

m, n, and q are each independently 0, 1 or 2;

p is 1 or 2;

W is selected from the group consisting of O, N(R⁷), C(O)N(R⁷), andSO_(q);

R⁶ is selected from the group consisting of carboxyl, alkylcarboxy,amido, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,heteroalkyl, acyl, and hydroxamic acid, any of which may be optionallysubstituted;

R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from thegroup consisting of hydrogen and optionally substituted lower alkyl;

R⁷ and R¹⁴ are independently selected from the group consisting ofhydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl, haloalkyl, andaminoalkyl; and

R¹⁵, R¹⁶, R¹⁸ and R¹⁹ are each independently selected from the groupconsisting of hydrogen, halogen, lower alkyl, haloalkyl, alkoxy,haloalkoxy, amino, aminoalkyl, aminoalkoxy and a bond.

In certain embodiments, compounds of the present invention havestructural Formula IV

wherein:

X³ is (CR¹⁸R¹⁹);

R¹ and R² are independently selected from the group consisting ofhydrogen, —(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl,alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl,alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted;

s is 1-8;

G¹ is selected from the group consisting of alkoxy, amino, amido,carbonyl, hydroxy, ether, an amino acid, and null;

G² is selected from the group consisting of alkyl, alkoxy, amino, aryl,halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino,guanidine, an amino acid, and null, any of which may be optionallysubstituted;

G³ is selected from the group consisting of alkyl, alkoxy, amino,hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted;

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, halogen, alkoxy and lower alkyl;

R⁵ is selected from the group consisting of —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)—and —(CR¹²R¹³)_(p)—;

m, n, and q are each independently 0, 1 or 2;

p is 1 or 2;

W is selected from the group consisting of O, N(R⁷), C(O)N(R⁷), andSO_(q);

R⁶ is selected from the group consisting of carboxyl, alkylcarboxy,amido, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,heteroalkyl, acyl, and hydroxamic acid, any of which may be optionallysubstituted;

R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from thegroup consisting of hydrogen and optionally substituted lower alkyl;

R⁷ and R¹⁴ are independently selected from the group consisting ofhydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl, haloalkyl, andaminoalkyl; and

R¹⁸ and R¹⁹ are each independently selected from the group consisting ofhydrogen, halogen, lower alkyl, haloalkyl, alkoxy, haloalkoxy, amino,aminoalkyl, aminoalkoxy and a bond.

In further embodiments, compounds of the present invention havestructural Formula V

wherein:

R¹ and R² are independently selected from the group consisting ofhydrogen, —(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl,alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl,alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted;

s is 1-8;

G¹ is selected from the group consisting of alkoxy, amino, amido,carbonyl, hydroxy, ether, an amino acid, and null;

G² is selected from the group consisting of alkyl, alkoxy, amino, aryl,halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino,guanidine, an amino acid, and null, any of which may be optionallysubstituted;

G³ is selected from the group consisting of alkyl, alkoxy, amino,hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted;

R⁵ is selected from the group consisting of —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)—and —(CR¹²R¹³)_(p)—;

m, n, and q are each independently 0, 1 or 2;

p is 1 or 2;

W is selected from the group consisting of O, N(R⁷), C(O)N(R⁷), andSO_(q);

R⁶ is selected from the group consisting of carboxyl, alkylcarboxy,amido, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,heteroalkyl, acyl, and hydroxamic acid, any of which may be optionallysubstituted;

R⁷ and R¹⁴ are independently selected from the group consisting ofhydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl, haloalkyl, andaminoalkyl; and

R¹⁹ is selected from the group consisting of hydrogen, halogen, loweralkyl and haloalkyl.

In yet further embodiments are provided compounds wherein R⁷ and R¹⁴ areindependently selected from the group consisting of hydrogen, halogenand optionally substituted lower alkyl

In yet further embodiments are provided compounds wherein R⁶ is selectedfrom the group consisting of aryl and heteroaryl, either of which may beoptionally substituted;

In yet further embodiments are provided compounds wherein R¹⁹ ishydrogen.

In yet further embodiments are provided compounds wherein R⁶ is selectedfrom the group consisting of phenyl, pyridine, pyrimidine, pyridazine,and pyrazine, any of which may be optionally substituted.

In yet further embodiments are provided compounds wherein R⁶ is selectedfrom the group consisting of phenyl, pyridine, and pyrimidine, any ofwhich may be optionally substituted.

In yet further embodiments are provided compounds wherein R¹⁴ ishydrogen.

In yet further embodiments are provided compounds wherein:

R⁵ is —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)—;

m and n are both 0;

W is N(R⁷); and

R⁷ is hydrogen.

In yet further embodiments are provided compounds wherein R⁶ has theformula

wherein

X⁴ is CR²⁰ or N;

X⁵ is CR²¹ or N;

X⁶ is CR²² or N;

X⁷ is CR²³ or N;

X⁸ is CR²⁴ or N;

wherein no more than two of X⁴-X⁸ may be N; and

R²⁰, R²¹, R²², R²³ and R²⁴ are independently selected from the groupconsisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy,lower haloalkyl, lower haloalkoxy, amino, and carboxyl.

In yet further embodiments are provided compounds wherein R⁶ has aformula selected from the group consisting of

In yet further embodiments are provided compounds wherein R² is loweralkyl. In yet further embodiments, R² is methyl.

In yet further embodiments are provided compounds wherein:

R¹ is selected from the group consisting of —(CH₂)_(s)G¹G²G³, loweralkyl, cycloalkyl, cycloalkylalkyl, and heterocycloalkyl, any of whichmay be optionally substituted;

s is 1-6;

G¹ is selected from the group consisting of amino, amido, and null;

G² is selected from the group consisting of alkoxy, aryl, halo,heterocycloalkyl, and null, any of which may be optionally substituted;and

G³ is selected from the group consisting of alkyl, carboxyl, and null,any of which may be optionally substituted.

In further embodiments, compounds of the present invention havestructural Formula VI

wherein:

R¹ and R² are independently selected from the group consisting ofhydrogen, —(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl,alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl,alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted;

s is 1-8;

G¹ is selected from the group consisting of alkoxy, amino, amido,carbonyl, hydroxy, ether, an amino acid, and null;

G² is selected from the group consisting of alkyl, alkoxy, amino, aryl,halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino,guanidine, an amino acid, and null, any of which may be optionallysubstituted;

G³ is selected from the group consisting of alkyl, alkoxy, amino,hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted; and

R²⁰ and R²⁴ are independently selected from the group consisting ofhydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lower haloalkyl,lower haloalkoxy, amino, and carboxyl.

In yet further embodiments, compounds of the present invention havestructural Formula VII

wherein:

R¹ and R² are independently selected from the group consisting ofhydrogen, —(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl,alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl,alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted;

s is 1-8;

G¹ is selected from the group consisting of alkoxy, amino, amido,carbonyl, hydroxy, ether, an amino acid, and null;

G² is selected from the group consisting of alkyl, alkoxy, amino, aryl,halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino,guanidine, an amino acid, and null, any of which may be optionallysubstituted;

G³ is selected from the group consisting of alkyl, alkoxy, amino,hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted; and

R²⁰, R²², and R²⁴ are independently selected from the group consistingof hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lowerhaloalkyl, lower haloalkoxy, amino, and carboxyl.

Compounds of the present invention may be selective amongst the PDE4isoforms PDE4A, PDE4B, PDE4C, and PDE4D in various ways. For example,compounds described herein may be selective for PDE4B and PDE4D over theother two isoforms, be a pan-inhibitor of all the isoforms, or beselective for only one isoform. In certain embodiments, compounds of thepresent invention may be selective for PDE4B over other isoforms.

The present invention also relates to a method of inhibiting at leastone PDE4 function comprising the step of contacting the PDE4 with acompound of Formula I, as described herein. The cell phenotype, cellproliferation, activity of PDE4, change in biochemical output producedby active PDE4, expression of PDE4, or binding of PDE4 with a naturalbinding partner may be monitored. Such methods may be modes of treatmentof disease, biological assays, cellular assays, biochemical assays, orthe like.

As used herein, the terms below have the meanings indicated.

When ranges of values are disclosed, and the notation “from n₁ . . . ton₂” is used, where n₁ and n₂ are the numbers, then unless otherwisespecified, this notation is intended to include the numbers themselvesand the range between them. This range may be integral or continuousbetween and including the end values. By way of example, the range “from2 to 6 carbons” is intended to include two, three, four, five, and sixcarbons, since carbons come in integer units. Compare, by way ofexample, the range “from 1 to 3 μM (micromolar),” which is intended toinclude 1 μM, 3 μM, and everything in between to any number ofsignificant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, or any other moiety were the atom attached to thecarbonyl is carbon. An “acetyl” group, which is a type of acyl, refersto a —C(O)CH₃ group. An “alkylcarbonyl” or “alkanoyl” group refers to analkyl group attached to the parent molecular moiety through a carbonylgroup. Examples of such groups include methylcarbonyl and ethylcarbonyl.Examples of acyl groups include formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkenyl will comprise from 2 to 6 carbon atoms. Theterm “alkenylene” refers to a carbon-carbon double bond system attachedat two or more positions such as ethenylene [(—CH═CH—), (—C::C—)].Examples of suitable alkenyl radicals include ethenyl, propenyl,2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwisespecified, the term “alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term alkyl is as defined below.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,and the like.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical containing from 1 to 20carbon atoms. In certain embodiments, said alkyl will comprise from 1 to10 carbon atoms. In further embodiments, said alkyl will comprise from 1to 6 carbon atoms. Alkyl groups may be optionally substituted as definedherein. Examples of alkyl radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl, noyl and the like. The term “alkylene,” as used herein,alone or in combination, refers to a saturated aliphatic group derivedfrom a straight or branched chain saturated hydrocarbon attached at twoor more positions, such as methylene (—CH₂—). Unless otherwisespecified, the term “alkyl” may include “alkylene” groups.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylidene,” as used herein, alone or in combination, refersto an alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether

(R—S—) radical wherein the term alkyl is as defined above and whereinthe sulfur may be singly or doubly oxidized. Examples of suitable alkylthioether radicals include methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl,” as used herein, alone or in combination, refers to astraight-chain or branched chain hydrocarbon radical having one or moretriple bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkynyl comprises from 2 to 6 carbon atoms. In furtherembodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term“alkynylene” refers to a carbon-carbon triple bond attached at twopositions such as ethynylene (—C:::C—, —C≡C—). Examples of alkynylradicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl,butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like.Unless otherwise specified, the term “alkynyl” may include “alkynylene”groups.

The terms “amido” and “carbamoyl,” as used herein, alone or incombination, refer to an amino group as described below attached to theparent molecular moiety through a carbonyl group, or vice versa. Theterm “C-amido” as used herein, alone or in combination, refers to a—C(═O)—N(R)₂ group with R as defined herein. The term “N-amido” as usedherein, alone or in combination, refers to a RC(═O)N(R′)— group, with Rand R′ as defined herein. The term “acylamino” as used herein, alone orin combination, embraces an acyl group attached to the parent moietythrough an amino group. An example of an “acylamino” group isacetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—N(R)(R′) or —N⁺(R)(R′)(R″), wherein R, R′ and R″ are independentlyselected from the group consisting of hydrogen, alkyl, acyl,heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any ofwhich may themselves be optionally substituted.

The term “amino acid,” as used herein, alone or in combination, means asubstituent of the form —NRCH(R′)C(O)OH, wherein R is typicallyhydrogen, but may be cyclized with N (for example, as in the case of theamino acid proline), and R′ is selected from the group consisting ofhydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, amino, amido, cycloalkylalkyl, heterocycloalkylalkyl,arylalkyl, heteroarylalkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, thiol,thioalkyl, alkylthioalkyl, and alkylthio, any of which may be optionallysubstituted. The term “amino acid” includes all naturally occurringamino acids as well as synthetic analogues.

The term “aryl,” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch rings may be attached together in a pendent manner or may be fused.The term “aryl” embraces aromatic radicals such as benzyl, phenyl,naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl,azulenyl, tetrahydronaphthyl, and biphenyl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein,alone or in combination, refers to an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, naphthoyl,phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent radical C₆H₄=derived from benzene. Examplesinclude benzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers toan ester of carbamic acid (—NHCOO—) which may be attached to the parentmolecular moiety from either the nitrogen or acid end, and which may beoptionally substituted as defined herein.

The term “O-carbamyl” as used herein, alone or in combination, refers toa —OC(O)NRR′, group, with R and R′ as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers toa ROC(O)NR′— group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxyl” or “carboxyl,” as used herein, refers to —C(O)OH,O-carboxy, C-carboxy, or the corresponding “carboxylate” anion, such asis in a carboxylic acid salt. An “O-carboxy” group refers to a RC(O)O—group, where R is as defined herein. A “C-carboxy” group refers to a—C(O)OR groups where R is as defined herein.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein,alone or in combination, refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl radical wherein each cyclicmoiety contains from 3 to 12 carbon atom ring members and which mayoptionally be a benzo fused ring system which is optionally substitutedas defined herein. In certain embodiments, said cycloalkyl will comprisefrom 5 to 7 carbon atoms. Examples of such cycloalkyl radicals includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like.“Bicyclic” and “tricyclic” as used herein are intended to include bothfused ring systems, such as decahydronaphthalene, octahydronaphthaleneas well as the multicyclic (multicentered) saturated or partiallyunsaturated type. The latter type of isomer is exemplified in generalby, bicyclo[1,1,1]pentane, camphor, adamantane, andbicyclo[3,2,1]octane.

The term “ester,” as used herein, alone or in combination, refers to acarboxyl group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, typicallyrefers to an oxy group bridging two moieties linked at carbon atoms.“Ether” may also include polyethers, such as, for example,—RO(CH₂)₂—O—(CH₂)₂—O—(CH₂)₂OR′, —RO(CH₂)₂—O—(CH₂)₂OR′, —RO(CH₂)₂OR′, and—RO(CH₂)₂OH.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the radical. Dihalo and polyhaloalkyl radicals may have two ormore of the same halo atoms or a combination of different halo radicals.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene (—CFH—),difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and the like.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or cyclic hydrocarbon radical,or combinations thereof, fully saturated or containing from 1 to 3degrees of unsaturation, consisting of the stated number of carbon atomsand from one to three heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N and S may be placed at any interior position of theheteroalkyl group. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃. The term heteroalkyl may include ethers.

The term “heteroaryl,” as used herein, alone or in combination, refersto 3 to 7 membered unsaturated heteromonocyclic rings, or fusedpolycyclic rings in which at least one of the fused rings isunsaturated, wherein at least one atom is selected from the groupconsisting of O, S, and N. In certain embodiments, said heteroaryl willcomprise from 5 to 7 carbon atoms. The term also embraces fusedpolycyclic groups wherein heterocyclic radicals are fused with arylradicals, wherein heteroaryl radicals are fused with other heteroarylradicals, or wherein heteroaryl radicals are fused with cycloalkylradicals. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl,imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl,indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl,benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl,benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl,tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclicheterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl,dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated monocyclic, bicyclic, ortricyclic heterocyclic radical containing at least one heteroatom asring members, wherein each said heteroatom may be independently selectedfrom the group consisting of nitrogen, oxygen, and sulfur In certainembodiments, said heterocycloalkyl will comprise from 1 to 4 heteroatomsas ring members. In further embodiments, said heterocycloalkyl willcomprise from 1 to 2 heteroatoms ring members. In certain embodiments,said heterocycloalkyl will comprise from 3 to 8 ring members in eachring. In further embodiments, said heterocycloalkyl will comprise from 3to 7 ring members in each ring. In yet further embodiments, saidheterocycloalkyl will comprise from 5 to 6 ring members in each ring.“Heterocycloalkyl” and “heterocycle” are intended to include sugars,sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, andcarbocyclic fused and benzo fused ring systems; additionally, both termsalso include systems where a heterocycle ring is fused to an aryl group,as defined herein, or an additional heterocycle group. Examples ofheterocycloalkyl groups include aziridinyl, azetidinyl,1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl,dihydrocinnolinyl, dihydrobenzodioxinyl,dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl,tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Theheterocycloalkyl groups may be optionally substituted unlessspecifically prohibited.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxamic acid” as used herein, refers to —C(O)ON(R)O(R′),wherein R and R′ are as defined herein, or the corresponding“hydroxamate” anion, including any corresponding hydroxamic acid salt.

The term “hydroxy,” as used herein, alone or in combination, refers to—OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group.

The term “imino,” as used herein, alone or in combination, refers to═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refersto ═N(OH) and

═N—O—.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently selected from carbon, nitrogen, oxygen andsulfur.

The term “lower,” as used herein, alone or in combination, meanscontaining from 1 to and including 6 carbon atoms.

The term “mercaptyl” as used herein, alone or in combination, refers toan RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in combination, refers to—NO₂.

The terms “oxy” or “oxa” as used herein, alone or in combination, referto —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The term “phosphoamide” as used herein, alone or in combination, refersto a phosphate group [(OH)₂P(O)O—] in which one or more of the hydroxylgroups has been replaced by nitrogen, amino, or amido.

The term “phosphonate” as used herein, alone or in combination, refersto a group of the form ROP(OR′)(OR)O— wherein R and R′ are selected fromthe group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl,cycloalkyl, heteroaryl, and heterocycloalkyl, any of which maythemselves be optionally substituted. “Phosphonate” includes “phosphate[(OH)₂P(O)O—] and related phosphoric acid anions which may form salts.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refers to the —SO₃H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—S(O)₂—.

The term “N-sulfonamido” refers to a RS(═O)₂NR′— group with R and R′ asdefined herein.

The term “S-sulfonamido” refers to a —S(═O)₂NRR′, group, with R and R′as defined herein.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl—C(S)H and in combination is a —C(S)— group.

The term “N-thiocarbamyl” refers to an ROC(S)NR′— group, with R and R′as defined herein.

The term “O-thiocarbamyl” refers to a —OC(S)NRR′, group with R and R′ asdefined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X₃CS(O)₂NR— group withX is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X₃CS(O)₂— group where X isa halogen.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

The term “trisubstituted silyl,” as used herein, alone or incombination, refers to a silicone group substituted at its three freevalences with groups as listed herein under the definition ofsubstituted amino. Examples include trimethysilyl,tert-butyldimethylsilyl, triphenylsilyl and the like.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that said groupis absent. A “null” group occurring between two other group may also beunderstood to be a collapsing of flanking groups. For example, if in—(CH₂)_(s)G¹G²G³, the element G² were null, said group would become—(CH₂)_(s)G¹G³.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H,pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Twosubstituents may be joined together to form a fused five-, six-, orseven-membered carbocyclic or heterocyclic ring consisting of zero tothree heteroatoms, for example forming methylenedioxy or ethylenedioxy.An optionally substituted group may be unsubstituted (e.g., —CH₂CH₃),fully substituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended.Additionally, different sets of optional substituents to a particularmoiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety selected fromthe group consisting of hydrogen, hydroxyl, halogen, alkyl, cycloalkyl,heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may beoptionally substituted. Such R and R′ groups should be understood to beoptionally substituted as defined herein. Whether an R group has anumber designation or not, every R group, including R, R′ and R^(n)where n=(1, 2, 3, . . . n), every substituent, and every term should beunderstood to be independent of every other in terms of selection from agroup. Should any variable, substituent, or term (e.g. aryl,heterocycle, R, etc.) occur more than one time in a formula or genericstructure, its definition at each occurrence is independent of thedefinition at every other occurrence. Those of skill in the art willfurther recognize that certain groups may be attached to a parentmolecule or may occupy a position in a chain of elements from either endas written. Thus, by way of example only, an unsymmetrical group such as—C(O)N(R)— may be attached to the parent moiety at either the carbon orthe nitrogen.

Asymmetric centers exist in the compounds of the present invention.These centers are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, and epimeric forms, aswell as d-isomers and l-isomers, and mixtures thereof. Individualstereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds of the present invention may exist as geometric isomers. Thepresent invention includes all cis, trans, syn, anti, entgegen (E), andzusammen (Z) isomers as well as the appropriate mixtures thereof.Additionally, compounds may exist as tautomers, including keto-enoltautomers; all tautomeric isomers are provided by this invention. By wayof example, the following pairs of tautomers illustrate how both formsare contemplated herein:

Additionally, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder” and“condition” (as in medical condition), in that all reflect an abnormalcondition of the body or of one of its parts that impairs normalfunctioning and is typically manifested by distinguishing signs andsymptoms.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each activeingredient. In addition, such administration also encompasses use ofeach type of therapeutic agent in a sequential manner. In either case,the treatment regimen will provide beneficial effects of the drugcombination in treating the conditions or disorders described herein.

“PDE4 inhibitor” is used herein to refer to a compound that exhibits anIC₅₀ with respect to PDE4 activity of no more than about 100 μM and moretypically not more than about 50 μM, as measured in the PDE4 assaydescribed generally hereinbelow. “IC₅₀” is that concentration ofinhibitor which reduces the activity of an enzyme (e.g., PDE4) tohalf-maximal level. Certain representative compounds of the presentinvention have been discovered to exhibit inhibition against PDE4. Incertain embodiments, compounds will exhibit an IC₅₀ with respect to PDE4of no more than about 10 μM; in further embodiments, compounds willexhibit an IC₅₀ with respect to PDE4 of no more than about 5 μM; in yetfurther embodiments, compounds will exhibit an IC₅₀ with respect to PDE4of not more than about 1 μM, as measured in the PDE4 assay describedherein. In yet further embodiments, compounds will exhibit an IC₅₀ withrespect to PDE4 of not more than about 200 nM.

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder.This amount will achieve the goal of reducing or eliminating the saiddisease or disorder.

As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis. The term “patient” means all mammals includinghumans. Examples of patients include humans, cows, dogs, cats, goats,sheep, pigs, and rabbits. Preferably, the patient is a human.

The term “prodrug” refers to a compound that is made more active invivo. Certain of the present compounds can also exist as prodrugs, asdescribed in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compoundsdescribed herein are structurally modified forms of the compound thatreadily undergo chemical changes under physiological conditions toprovide the compound. Additionally, prodrugs can be converted to thecompound by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to a compound when placedin a transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the compound, or parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A wide variety of prodrug derivativesare known in the art, such as those that rely on hydrolytic cleavage oroxidative activation of the prodrug. An example, without limitation, ofa prodrug would be a compound which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound. The term “therapeutically acceptable prodrug,” refers to thoseprodrugs or zwitterions which are suitable for use in contact with thetissues of patients without undue toxicity, irritation, and allergicresponse, are commensurate with a reasonable benefit/risk ratio, and areeffective for their intended use.

The compounds of the present invention can exist as therapeuticallyacceptable salts. The present invention includes compounds listed abovein the form of salts, including acid addition salts. Suitable saltsinclude those formed with both organic and inorganic acids. Such acidaddition salts will normally be pharmaceutically acceptable. However,salts of non-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Basic additionsalts may also be formed and be pharmaceutically acceptable. For a morecomplete discussion of the preparation and selection of salts, refer toPharmaceutical Salts: Properties, Selection, and Use (Stahl, P.Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds of the present inventionwhich are water or oil-soluble or dispersible and therapeuticallyacceptable as defined herein. The salts can be prepared during the finalisolation and purification of the compounds or separately by reactingthe appropriate compound in the form of the free base with a suitableacid. Representative acid addition salts include acetate, adipate,alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, succinate, sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds of the present invention can be quaternized withmethyl, ethyl, propyl, and butyl chlorides, bromides, and iodides;dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl,myristyl, and steryl chlorides, bromides, and iodides; and benzyl andphenethyl bromides. Examples of acids which can be employed to formtherapeutically acceptable addition salts include inorganic acids suchas hydrochloric, hydrobromic, sulfuric, and phosphoric, and organicacids such as oxalic, maleic, succinic, and citric. Salts can also beformed by coordination of the compounds with an alkali metal or alkalineearth ion. Hence, the present invention contemplates sodium, potassium,magnesium, and calcium salts of the compounds disclosed herein, and thelike.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxyl group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

While it may be possible for the compounds of the subject invention tobe administered as the raw chemical, it is also possible to present themas a pharmaceutical formulation. Accordingly, provided herein arepharmaceutical formulations which comprise one or more of certaincompounds of the present invention, or one or more pharmaceuticallyacceptable salts, esters, prodrugs, amides, or solvates thereof,together with one or more pharmaceutically acceptable carriers thereofand optionally one or more other therapeutic ingredients. The carrier(s)must be “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof. Proper formulation is dependent upon the route ofadministration chosen. Any of the well-known techniques, carriers, andexcipients may be used as suitable and as understood in the art; e.g.,in Remington's Pharmaceutical Sciences. The pharmaceutical compositionsdisclosed herein may be manufactured in any manner known in the art,e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orcompression processes.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal, rectaland topical (including dermal, buccal, sublingual and intraocular)administration although the most suitable route may depend upon forexample the condition and disorder of the recipient. The formulationsmay conveniently be presented in unit dosage form and may be prepared byany of the methods well known in the art of pharmacy. Typically, thesemethods include the step of bringing into association a compound of thesubject invention or a pharmaceutically acceptable salt, ester, amide,prodrug or solvate thereof (“active ingredient”) with the carrier whichconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The formulations may be presentedin unit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds of the present invention may be administeredtopically, that is by non-systemic administration. This includes theapplication of a compound of the present invention externally to theepidermis or the buccal cavity and the instillation of such a compoundinto the ear, eye and nose, such that the compound does notsignificantly enter the blood stream. In contrast, systemicadministration refers to oral, intravenous, intraperitoneal andintramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as gels, liniments, lotions, creams,ointments or pastes, and drops suitable for administration to the eye,ear or nose. The active ingredient for topical administration maycomprise, for example, from 0.001% to 10% w/w (by weight) of theformulation. In certain embodiments, the active ingredient may compriseas much as 10% w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/wof the formulation.

Gels for topical or transdermal administration may comprise, generally,a mixture of volatile solvents, nonvolatile solvents, and water. Incertain embodiments, the volatile solvent component of the bufferedsolvent system may include lower (C1-C6) alkyl alcohols, lower alkylglycols and lower glycol polymers. In further embodiments, the volatilesolvent is ethanol. The volatile solvent component is thought to act asa penetration enhancer, while also producing a cooling effect on theskin as it evaporates. The nonvolatile solvent portion of the bufferedsolvent system is selected from lower alkylene glycols and lower glycolpolymers. In certain embodiments, propylene glycol is used. Thenonvolatile solvent slows the evaporation of the volatile solvent andreduces the vapor pressure of the buffered solvent system. The amount ofthis nonvolatile solvent component, as with the volatile solvent, isdetermined by the pharmaceutical compound or drug being used. When toolittle of the nonvolatile solvent is in the system, the pharmaceuticalcompound may crystallize due to evaporation of volatile solvent, whilean excess may result in a lack of bioavailability due to poor release ofdrug from solvent mixture. The buffer component of the buffered solventsystem may be selected from any buffer commonly used in the art; incertain embodiments, water is used. A common ratio of ingredients isabout 20% of the nonvolatile solvent, about 40% of the volatile solvent,and about 40% water. There are several optional ingredients which can beadded to the topical composition. These include, but are not limited to,chelators and gelling agents. Appropriate gelling agents can include,but are not limited to, semisynthetic cellulose derivatives (such ashydroxypropylmethylcellulose) and synthetic polymers, and cosmeticagents.

Lotions include those suitable for application to the skin or eye. Aneye lotion may comprise a sterile aqueous solution optionally containinga bactericide and may be prepared by methods similar to those for thepreparation of drops. Lotions or liniments for application to the skinmay also include an agent to hasten drying and to cool the skin, such asan alcohol or acetone, and/or a moisturizer such as glycerol or an oilsuch as castor oil or arachis oil.

Creams, ointments or pastes are semi-solid formulations of the activeingredient for external application. They may be made by mixing theactive ingredient in finely-divided or powdered form, alone or insolution or suspension in an aqueous or non-aqueous fluid, with the aidof suitable machinery, with a greasy or non-greasy base. The base maycomprise hydrocarbons such as hard, soft or liquid paraffin, glycerol,beeswax, a metallic soap; a mucilage; an oil of natural origin such asalmond, corn, arachis, castor or olive oil; wool fat or its derivativesor a fatty acid such as stearic or oleic acid together with an alcoholsuch as propylene glycol or a macrogel. The formulation may incorporateany suitable surface active agent such as an anionic, cationic ornon-ionic surfactant such as a sorbitan ester or a polyoxyethylenederivative thereof. Suspending agents such as natural gums, cellulosederivatives or inorganic materials such as silicaceous silicas, andother ingredients such as lanolin, may also be included.

Drops may comprise sterile aqueous or oily solutions or suspensions andmay be prepared by dissolving the active ingredient in a suitableaqueous solution of a bactericidal and/or fungicidal agent and/or anyother suitable preservative, and, in certain embodiments, including asurface active agent. The resulting solution may then be clarified byfiltration, transferred to a suitable container which is then sealed andsterilized by autoclaving or maintaining at 98-100° C. for half an hour.Alternatively, the solution may be sterilized by filtration andtransferred to the container by an aseptic technique. Examples ofbactericidal and fungicidal agents suitable for inclusion in the dropsare phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride(0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for thepreparation of an oily solution include glycerol, diluted alcohol andpropylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia.

For administration by inhalation, compounds may be convenientlydelivered from an insufflator, nebulizer pressurized packs or otherconvenient means of delivering an aerosol spray. Pressurized packs maycomprise a suitable propellant such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form, in for example, capsules, cartridges,gelatin or blister packs from which the powder may be administered withthe aid of an inhalator or insufflator.

Preferred unit dosage formulations are those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations described above may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Compounds may be administered orally or via injection at a dose of from0.1 to 500 mg/kg per day. The dose range for adult humans is generallyfrom 5 mg to 2 g/day. Tablets or other forms of presentation provided indiscrete units may conveniently contain an amount of one or morecompounds which is effective at such dosage or as a multiple of thesame, for instance, units containing 5 mg to 500 mg, usually around 10mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The compounds can be administered in various modes, e.g. orally,topically, or by injection. The precise amount of compound administeredto a patient will be the responsibility of the attendant physician. Thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diets, time ofadministration, route of administration, rate of excretion, drugcombination, the precise disorder being treated, and the severity of theindication or condition being treated. Also, the route of administrationmay vary depending on the condition and its severity.

In certain instances, it may be appropriate to administer at least oneof the compounds described herein (or a pharmaceutically acceptablesalt, ester, or prodrug thereof) in combination with another therapeuticagent. By way of example only, if one of the side effects experienced bya patient upon receiving one of the compounds herein is hypertension,then it may be appropriate to administer an anti-hypertensive agent incombination with the initial therapeutic agent. Or, by way of exampleonly, the therapeutic effectiveness of one of the compounds describedherein may be enhanced by administration of an adjuvant (i.e., by itselfthe adjuvant may only have minimal therapeutic benefit, but incombination with another therapeutic agent, the overall therapeuticbenefit to the patient is enhanced). Or, by way of example only, thebenefit of experienced by a patient may be increased by administeringone of the compounds described herein with another therapeutic agent(which also includes a therapeutic regimen) that also has therapeuticbenefit. By way of example only, in a treatment for diabetes involvingadministration of one of the compounds described herein, increasedtherapeutic benefit may result by also providing the patient withanother therapeutic agent for diabetes. In any case, regardless of thedisease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

In any case, the multiple therapeutic agents (at least one of which is acompound of the present invention) may be administered in any order oreven simultaneously. If simultaneously, the multiple therapeutic agentsmay be provided in a single, unified form, or in multiple forms (by wayof example only, either as a single pill or as two separate pills). Oneof the therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may be any duration of time ranging from a few minutes tofour weeks.

Thus, in another aspect, the present invention provides methods fortreating PDE4-mediated disorders in a human or animal subject in need ofsuch treatment comprising administering to said subject an amount of acompound of the present invention effective to reduce or prevent saiddisorder in the subject in combination with at least one additionalagent for the treatment of said disorder that is known in the art. In arelated aspect, the present invention provides therapeutic compositionscomprising at least one compound of the present invention in combinationwith one or more additional agents for the treatment of PDE4-mediateddisorders.

Compounds of the subject invention may be useful in treatingPDE4-mediated disease, disorders and conditions. In certain embodiments,said compounds may find use in treating acute and chronic pain andinflammation. The compounds of the present invention may be useful totreat patients with neuropathy, neuropathic pain, or inflammatory painsuch as reflex sympathetic dystrophy/causalgia (nerve injury),peripheral neuropathy (including diabetic neuropathy), intractablecancer pain, complex regional pain syndrome, and entrapment neuropathy(carpel tunnel syndrome). The compounds may also be useful in thetreatment of pain associated with acute herpes zoster (shingles),postherpetic neuralgia (PHN), and associated pain syndromes such asocular pain. The compounds may further be useful as analgesics in thetreatment of pain such as surgical analgesia, or as an antipyretic forthe treatment of fever. Pain indications include, but are not limitedto, post-surgical pain for various surgical procedures includingpost-cardiac surgery, dental pain/dental extraction, pain resulting fromcancer, muscular pain, mastalgia, pain resulting from dermal injuries,lower back pain, headaches of various etiologies, including migraine,and the like. The compounds may also be useful for the treatment ofpain-related disorders such as tactile allodynia and hyperalgesia. Thepain may be somatogenic (either nociceptive or neuropathic), acuteand/or chronic. The PDE4 inhibitors of the subject invention may also beuseful in conditions where NSAIDs, morphine or fentanyl opiates and/orother opioid analgesics would traditionally be administered.

Furthermore, compounds of the subject invention may be used in thetreatment or prevention of opiate tolerance in patients needingprotracted opiate analgesics, and benzodiazepine tolerance in patientstaking benzodiazepines, and other addictive behavior, for example,nicotine addiction, alcoholism, and eating disorders. Moreover, thecompounds and methods of the present invention may be useful in thetreatment or prevention of drug withdrawal symptoms, for exampletreatment or prevention of symptoms of withdrawal from opiate, alcohol,or tobacco addiction.

In addition, compounds of the subject invention may be used to treatinsulin resistance and other metabolic disorders such as atherosclerosisthat are typically associated with an exaggerated inflammatorysignaling.

The present invention encompasses therapeutic methods using novelselective PDE4 inhibitors to treat or prevent respiratory disease orconditions, including therapeutic methods of use in medicine forpreventing and treating a respiratory disease or condition including:asthmatic conditions including allergen-induced asthma, exercise-inducedasthma, pollution-induced asthma, cold-induced asthma, andviral-induced-asthma; asthma-related diseases such as airwayhyperreactivity and small airway disease; chronic obstructive pulmonarydiseases including chronic bronchitis with normal airflow, chronicbronchitis with airway obstruction (chronic obstructive bronchitis),emphysema, asthmatic bronchitis, and bullous disease; and otherpulmonary diseases involving inflammation including bronchiolitis,bronchioectasis, cystic fibrosis, pigeon fancier's disease, farmer'slung, acute respiratory distress syndrome, pneumonia, pneumonitis,aspiration or inhalation injury, fat embolism in the lung, acidosisinflammation of the lung, acute pulmonary edema, acute mountainsickness, acute pulmonary hypertension, persistent pulmonaryhypertension of the newborn, perinatal aspiration syndrome, hyalinemembrane disease, acute pulmonary thromboembolism, heparin-protaminereactions, sepsis, status asthamticus, hypoxia, dyspnea, hypercapnea,hyperinflation, hypoxemia, and cough. Further, compounds disclosedherein would find use in the treatment of allergic disorders such asdelayed type hypersensitivity reaction, allergic contact dermatitis,allergic rhinitis, and chronic sinusitis.

Other disorders or conditions which may be treated by the compounds ofthe present invention include inflammation and related disorders. Thecompounds of the present invention may be useful as anti-inflammatoryagents with the additional benefit of having significantly less harmfulside effects. The compounds may be useful to treat arthritis, includingbut not limited to rheumatoid arthritis, spondyloarthropathies, goutyarthritis, osteoarthritis, juvenile arthritis, acute rheumaticarthritis, enteropathic arthritis, neuropathic arthritis, psoriaticarthritis, reactive arthritis (Reiter's syndrome), and pyogenicarthritis, and autoimmune diseases, including systemic lupuserythematosus, hemolytic syndromes, autoimmune hepatitis, autoimmuneneuropathy, vitiglio (autoimmune thyroiditis), Hashimoto's thyroiditis,anemias, myositis including polymyositis, alopecia greata, Goodpasture'ssyndrome, hypophytis, and pulmonary fibrosis.

The compounds may also be useful in treating osteoporosis and otherrelated bone disorders.

These compounds may also be used to treat gastrointestinal conditionssuch as reflux esophagitis, diarrhea, inflammatory bowel disease,Crohn's disease, gastritis, irritable bowel syndrome, Graves' disease(hyperthyroidism), necrotizing enterocolitis, and ulcerative colitis.The compounds may also be used in the treatment of pulmonaryinflammation, such as that associated with viral infections and cysticfibrosis.

In addition, compounds of invention may also be useful in organtransplant patients either alone or in combination with conventionalimmunomodulators. Examples of conditions to be treated in said patientsinclude graft vs. host reaction (i.e., graft vs. host disease),allograft rejections (e.g., acute allograft rejection, and chronicallograft rejection), transplant reperfusion injury, and earlytransplantation rejection (e.g., acute allograft rejection).

Yet further, the compounds of the invention may be useful in thetreatment of pruritis and vitaligo.

The compounds of the present invention may also be useful in treatingtissue damage in such diseases as vascular diseases, migraine headaches,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, rheumatic fever, type I diabetes, neuromuscular junctiondisease including myasthenia gravis, white matter disease includingmultiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome,Langerhans' cell histiocytosis, glomerulonephritis, reperfusion injury,pancreatitis, interstitial cystitis, Behcet's syndrome, polymyositis,gingivitis, periodontis, hypersensitivity, swelling occurring afterinjury, ischemias including myocardial ischemia, cardiovascularischemia, and ischemia secondary to cardiac arrest, cirrhosis, septicshock, endotoxic shock, gram negative sepsis, toxic shock syndrome,stroke, ischemia reperfusion injury, multi-organ dysfunction, restenosisincluding restenosis following coronary bypass surgery, and the like.

The compounds of the subject invention may also be useful for thetreatment of certain diseases and disorders of the nervous system.Central nervous system disorders in which PDE4 inhibition may be usefulinclude cortical dementias including Alzheimer's disease and mildcognitive impairment (MCI), central nervous system damage resulting fromstroke, ischemias including cerebral ischemia (both focal ischemia,thrombotic stroke and global ischemia (for example, secondary to cardiacarrest), and trauma. Neurodegenerative disorders in which PDE4inhibition may be useful include nerve degeneration or nerve necrosis indisorders such as hypoxia, hypoglycemia, epilepsy, and in cases ofcentral nervous system (CNS) trauma (such as spinal cord and headinjury), hyperbaric oxygen convulsions and toxicity, dementia e.g.pre-senile dementia, and AIDS-related dementia, cachexia, Sydenham'schorea, Huntington's disease, Parkinson's Disease, amyotrophic lateralsclerosis (ALS), Korsakoff's syndrome, and imbecility relating to acerebral vessel disorder. Further disorders in which PDE4 inhibitionmight prove useful include neuropathies of the central and peripheralnervous system (including, for example, IgA neuropathy, membranousneuropathy and idiopathic neuropathy), chronic inflammatorydemyelinating polyneuropathy, transverse myelitis, Gullain-Barredisease, encephalitis, and cancers of the nervous system. Disorders ofCNS function in which PDE4 inhibitors may find use include sleepingdisorders, schizophrenia, depression, depression or other symptomsassociated with Premenstrual Syndrome (PMS), and anxiety.

Furthermore, the compounds of the present invention may also be usefulin inhibiting PDE4 activity for the amelioration of systemic disordersincluding systemic hypotension associated with septic and/or toxichemorrhagic shock induced by a wide variety of agents; as a therapy withcytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short termimmunosuppression in transplant therapy.

Still other disorders or conditions which may be treated by thecompounds of the subject invention include the prevention or treatmentof cancer, such as colorectal cancer, and cancer of the breast, lung,prostate, bladder, cervix and skin. Compounds of the invention may beused in the treatment and prevention of neoplasias including but notlimited to brain cancer, bone cancer, leukemia, lymphoma, epithelialcell-derived neoplasia (epithelial carcinoma) such as basal cellcarcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer,mouth cancer, esophageal cancer, small bowel cancer and stomach cancer,colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarycancer, cervical cancer, lung cancer, breast cancer and skin cancer,such as squamous cell and basal cell cancers, prostate cancer, renalcell carcinoma, and other known cancers that effect epithelial cellsthroughout the body. The neoplasia can be selected from gastrointestinalcancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer,prostate cancer, cervical cancer, lung cancer, breast cancer and skincancer, such as squamous cell and basal cell cancers. The presentcompounds and methods may also be used to treat the fibrosis whichoccurs with radiation therapy. The present compounds and methods may beused to treat subjects having adenomatous polyps, including those withfamilial adenomatous polyposis (FAP). Additionally, the presentcompounds and methods may be used to prevent polyps from forming inpatients at risk of FAP.

The compounds of the subject invention may be used in the treatment ofophthalmic diseases, such as dry eye, glaucoma, cornealneovascularization, optic neuritis, Sjogren's syndrome, retinal gangliondegeneration, ocular ischemia, retinitis, retinopathies, uveitis, ocularphotophobia, and of inflammation and pain associated with acute injuryto the eye tissue. Specifically, the compounds may be used to treatglaucomatous retinopathy and/or diabetic retinopathy. The compounds mayalso be used to treat post-operative inflammation or pain as fromophthalmic surgery such as cataract surgery and refractive surgery.

Moreover, compounds of the subject invention may be used in thetreatment of menstrual cramps, dysmenorrhea, premature labor,endometriosis, tendonitis, bursitis, skin-related conditions such aspsoriasis, eczema, burns, sunburn, dermatitis, pancreatitis, hepatitis,lichen planus, scleritis, scleroderma, dermatomyositis, and the like.Other conditions in which the compounds of the subject invention may beused include diabetes (type I or type II), atherosclerosis, congestiveheart failure, myocarditis, atherosclerosis, cerebral ischemia,angiogenesis, pulmonary hypertension, and aortic aneurysm.

The present compounds may also be used in co-therapies, partially orcompletely, in place of other conventional anti-inflammatory therapies,such as together with steroids, NSAIDs, COX-2 selective inhibitors,5-lipoxygenase inhibitors, LTB₄ antagonists and LTA₄ hydrolaseinhibitors. The compounds of the subject invention may also be used toprevent tissue damage when therapeutically combined with antibacterialor antiviral agents.

Besides being useful for human treatment, the compounds and formulationsof the present invention are also useful for veterinary treatment ofcompanion animals, exotic animals and farm animals, including mammals,rodents, and the like. More preferred animals include horses, dogs, andcats.

General Synthetic Methods for Preparing Compounds

The following schemes can be used to practice the present invention.

The invention is further illustrated by the following examples.

EXAMPLE 18-(Cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

Step 1

Sulfuric acid (3.0 mL, 56 mmol) was added dropwise over 2 min to asolution of methyl 3-hydroxy-4-methoxybenzoate (3.64 g, 20 mmol),tetrabutylammonium hydrogensulfate (340 mg, 1.0 mmol), isopropyl nitrate(5.0 mL, 50 mmol), and dichloromethane (40 mL) at 0° C. The reaction wasallowed to warm to rt, maintained for 45 min, and then quenched with icewater (100 mL). This mixture was extracted with dichloromethane (250mL×2). The combined extracts were dried, filtered, concentrated, andpurified by silica gel chromatography (4:1→3:7; hexanes:ethyl acetate)to give methyl 3-hydroxy-4-methoxy-2-nitrobenzoate: MS (ESI): 228.4.

Step 2

A mixture of methyl 3-hydroxy-4-methoxy-2-nitrobenzoate (1.14 g, 5.0mmol), bromocyclopentane (0.7 mL, 6.5 mmol), potassium carbonate (2.0 g,14 mmol), and anhydrous acetonitrile (15 mL) was refluxed under N₂.After 19 h, the reaction was allowed to cool to rt, concentrated, andpurified by silica gel chromatography (4:1→3:2; hexanes:ethyl acetate)to give methyl 3-(cyclopentyloxy)-4-methoxy-2-nitrobenzoate: MS (ESI):296.5.

Step 3

A mixture of methyl 3-(cyclopentyloxy)-4-methoxy-2-nitrobenzoate (750mg, 2.54 mmol), 10% Pd/C (50% H₂O, 500 mg, 0.23 mmol Pd), and methanol(10 mL) was stirred vigorously at rt under an atmosphere of H₂. After 21h, the mixture was filtered through Celite and concentrated to givemethyl 2-amino-3-(cyclopentyloxy)-4-methoxybenzoate: MS (ESI): 266.5.

Step 4

A solution of methyl 2-amino-3-(cyclopentyloxy)-4-methoxybenzoate (5.54g, 20.9 mmol), acetic anhydride (21.0 mL, 222 mmol), and dioxane (35 mL)was heated at 40° C. under N₂ for 17 h and then allowed to cool to rt.Water (10 mL) was added, and after 15 min of stirring, the reaction wasconcentrated to give methyl2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate: MS (ESI): 307.9.

Step 5

A solution of methyl 2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate(6.42 g, 20.9 mmol) and anhydrous THF (60 mL) was added via syringe pump(1 mL/min) to a solution of KHMDS (150 mL, 0.5M PhMe, 75 mmol) at −78°C. under N₂. The reaction was allowed to slowly warm to rt as the bathexpired overnight. After 17 h, the reaction was poured into ice/water(250 mL), let stir for 10 min, and the layers were separated. Theaqueous was washed with ether (150 mL), acidified with conc. HCl (7 mL),and filtered to give8-(cyclopentyloxy)-4-hydroxy-7-methoxyquinolin-2(1H)-one: MS (ESI):276.0.

Step 6

A mixture of 8-(cyclopentyloxy)-4-hydroxy-7-methoxyquinolin-2(1H)-one(350 mg, 1.3 mmol), ammonium acetate (4.0 g, 52 mmol), and anhydrousm-xylene (10 mL) was heated at 150° C. under N₂ for 48 h and thenallowed to cool to rt. The mixture was concentrated to dryness, dilutedwith water (25 mL), stirred for 2 min, sonicated for 1 min, and thenstirred for 5 min. The free-flowing solid was filtered, washed withwater (25 mL), and pumped to dryness to give4-amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one: MS (ESI): 274.9.

Step 7

4-Amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one (340 mg, 1.24mmol) was added in 3 portions over 5 min to a mixture of sodium hydride(110 mg, 60%, 2.75 mmol) and DMSO (4 mL) at rt under N₂. After 5 min,3,4,5-trichloropyridine (271 mg, 1.49 mmol) was added. After 19 h, moresodium hydride (100 mg, 60%, 2.5 mmol) was added followed by more3,4,5-trichloropyridine (250 mg, 1.37 mmol). After an additional 4 h,the reaction was poured into 1M KH₂PO₄ (75 mL) and stirred for 5 min.The solids were filtered, washed with water (25 mL), and then purifiedby reverse-phase HPLC (3:7→1:0; acetonitrile:water). In some cases,additional purification by silica gel chromatography (1:0→9:1;dichlormethane:methanol) was needed to give8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.86 (s, 1H), 8.76 (s, 2H),7.87 (d, 1H), 7.06 (d, 1H), 4.97 (m, 1H), 4.78 (s, 1H), 3.90 (s, 3H),1.83-1.48 (m, 8H); MS (ESI): 419.7.

EXAMPLE 28-(Cyclopentyloxy)-4-(3,5-dichloropyridin-4-yloxy)-7-methoxyquinolin-2(1H)-one

The title compound was isolated from the purification of Example 1, Step7. ¹H NMR (400 MHz, DMSO-d₆): δ 10.28 (s, 1H), 8.84 (s, 2H), 7.71 (d,1H), 7.11 (d, 1H), 5.35 (s, 1H), 4.97 (m, 1H), 3.91 (s, 3H), 1.86-1.43(m, 8H); MS (ESI): 420.7.

EXAMPLE 38-(Cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from methyl3-hydroxy-4-methoxy-2-nitrobenzoate (Example 1, Step 1) and(bromomethyl)cyclopropane following the procedures outlined inExample 1. ¹H NMR (400 MHz, DMSO-d₆): δ 9.91 (s, 1H), 8.83 (s, 1H), 8.76(s, 2H), 7.87 (d, 1H), 7.03 (d, 1H), 4.78 (s, 1H), 3.89 (s, 3H), 3.84(d, 2H), 1.27 (m, 1H), 0.45 (m, 2H), 0.25 (m, 2H); MS (ESI): 405.8.

EXAMPLE 48-(Cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-1-methylquinolin-2(1H)-one

Step 1

A solution of methyl 2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate(1.6 g, 5.2 mmol, Example 1, Step 4) and anhydrous THF (30 mL) was addedover 5 min to a mixture of sodium hydride (230 mg, 5.75 mmol) andanhydrous THF (10 mL) at 0° C. under N₂. The reaction was allowed towarm to rt and after 20 min, cooled back to 0° C. A solution ofiodomethane (1.06 g, 0.0075 mol) and anhydrous THF (10 mL) was addedover 3 min. The reaction was allowed to warm to rt and after 30 min,concentrated. The residue was diluted with ethyl acetate (40 mL) andwashed with brine (10 mL×2). The organic layer was dried, filtered, andconcentrated to give methyl3-(cyclopentyloxy)-4-methoxy-2-(N-methylacetamido)benzoate: MS (ESI):322.1.

Step 2

The title compound was prepared from methyl3-(cyclopentyloxy)-4-methoxy-2-(N-methylacetamido)benzoate following theprocedures outlined in Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (s,1H), 8.74 (s, 2H), 7.92 (d, 1H), 7.13 (d, 1H), 4.92 (s, 1H), 4.53 (m,1H), 3.90 (s, 3H), 3.59 (s, 3H), 1.80-1.48 (m, 8H); MS (ESI): 433.9.

EXAMPLE 58-(Cyclopentyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from 4-bromo-3,5-dimethylpyridine and4-amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one (Example 1, Step6) following the procedure outlined in Example 8. ¹H NMR (400 MHz,DMSO-d₆): δ 9.08 (s, 1H), 8.44 (s, 1H), 8.40 (s, 2H), 7.88 (d, 1H), 7.03(d, 1H), 4.96 (m, 1H), 4.51 (s, 1H), 3.90 (s, 3H), 2.13 (s, 6H),1.80-1.54 (m, 8H); MS (ESI): 380.2.

EXAMPLE 61,3-Dibromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

N-Bromosuccinimide (0.118 g, 0.61 mmol) was added to a solution of4-(3,5-dichloropyridin-4-ylamino)-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one(0.100 g, 0.240 mmol, Example 1) and anhydrous DMF (2 mL) at 0° C. After2 h at 0° C., the mixture was poured into water, and the precipitate wasfiltered to give1,3-dibromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 10.5 (s, 1H), 8.59 (s, 2H), 6.76 (d, 1H),6.61 (d, 1H), 4.87 (m, 1H), 3.80 (s, 3H), 1.82-1.51 (m, 8H); MS (ESI):575.8.

EXAMPLE 73-Bromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

N-Bromosuccinimide (0.104 g, 0.585 mmol) was added to a solution of4-(3,5-dichloropyridin-4-ylamino)-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one(0.246 g, 0.585 mmol, Example 1) and anhydrous DMF (3 mL) at 0° C. After4 h at 0° C., the mixture was poured into water, and the precipitate wasfiltered. Saturated sodium thiosulfate solution (1 mL) was added to asolution of the filter cake and methanol (5 mL). After the dibromointermediate was consumed by LCMS, the mixture was diluted with waterand extracted with EtOAc. The organic extract was dried, filtered, andconcentrated to give3-bromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 8.88 (br s, 1H), 8.42 (s,2H), 7.62 (d, 1H), 7.04 (d, 1H), 4.98 (m, 1H), 3.89 (s, 3H), 1.84-1.51(m, 8H); MS (ESI): 497.8.

EXAMPLE 88-(Cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

A solution of 4-bromo-3,5-dimethylpyridine (1.16 g, 6.21 mmol) anddegassed toluene (5 mL) was added to a mixture of4-amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one (1.94 g, 7.45mmol, intermediate for Example 3), Pd₂(dba)₃, (0.28 g, 0.31 mmol),2,2-dicyclohexylphosphorane triisopropylbiphenyl (0.59 g, 1.24 mmol),sodium tert-butoxide (1.20 g, 12.4 mmol), and degassed toluene (20 mL)under N₂. The mixture was heated at 110° C. for 2 h, allowed to cool tort, sonicated until the solids broke up, and then filtered throughCelite with EtOAc (500 mL). The filtrate was concentrated, purified bysilica gel chromatography (0→8% MeOH/CH₂Cl₂), and then repurified byreverse-phase HPLC (25→100% MeCN/H₂O) to give8-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 9.64 (s, 1H), 8.43 (s, 1H), 8.42 (s, 2H),7.89 (d, 1H), 7.03 (d, 1H), 4.54 (s, 1H), 3.91 (s, 3H), 3.85 (d, 2H),2.15 (s, 6H), 1.28 (m, 1H), 0.47 (m, 2H), 0.28 (m, 2H); MS (ESI): 365.8.

EXAMPLE 98-(Cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-1-(2-hydroxyethyl)-7-methoxyquinolin-2(1H)-one

Step 1

Methyl3-(cyclopentyloxy)-4-methoxy-2-(N-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido)benzoatewas prepared from methyl2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate (Example 1, Step 4)following the procedure outlined in Example 4 (except: solvent was DMF;temp was 33° C.; time was overnight). MS (ESI): 458.2 (M+Na).

Step 2

8-(Cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)quinolin-2(1H)-onewas prepared from methyl3-(cyclopentyloxy)-4-methoxy-2-(N-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido)benzoatefollowing the procedures outlined in Example 1. MS (ESI): 570 (M+Na).

Step 3

p-Toluenesulfonic acid (172 mg, 1.0 mmol) was added to a solution of8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)quinolin-2(1H)-one(2.4 g, 4.4 mmol) and methanol (100 mL). After stirring overnight, thereaction was concentrated, diluted with dichloromethane (100 mL), andthen washed with sat'd NaHCO₃ (20 mL) followed by water (20 mL). Theorganic layer was dried, filtered, concentrated, and recrystallized fromdichloromethane/petroleum ether (1:2) to give8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-1-(2-hydroxyethyl)-7-methoxyquinolin-2(1H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 8.74 (s, 2H), 8.73 (s, 1H), 7.91 (d, 1H),7.11 (d, 1H), 4.92 (s, 1H), 4.65 (t, 2H), 4.59 (m, 1H), 4.50 (t, 1H),3.90 (s, 3H), 3.32 (m 2H), 1.80-1.48 (m, 8H); MS (ESI): 463.9.

EXAMPLE 108-(Cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-1-(2-(dimethylamino)ethyl)-7-methoxyquinolin-2(1H)-one

Step 1

Dess-Martin periodinane (933 mg, 2.2 mmol) was added to a solution of8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-1-(2-hydroxyethyl)-7-methoxyquinolin-2(1H)-one(500 mg, 1.08 mmol, Example 9) and CH₂Cl₂ (30 mL) at 0° C. After 30 min,the mixture was allowed to warm to rt. When the starting material wasconsumed, the reaction was diluted with dichloromethane (25 mL), washedwith aq. NaOH (20 mL×2), and then washed with water (20 mL). The organiclayer was dried, filtered, concentrated, and purified by silica gelchromatography (1:2→1:1; ethyl acetate:petroleum ether) to give2-(8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde:MS (ESI): 462.2.

Step 2

Titanium (IV) isopropoxide (496 mg, 1.74 mmol) and2-(8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde(400 mg, 0.87 mmol) were added sequentially to a solution ofdimethylamine hydrochloride (144 mg, 1.74 mmol), triethylamine (176 mg,1.74 mmol), and absolute ethanol (20 mL). After stirring overnight,sodium borohydride (50 mg, 1.3 mmol) was added. After an additional 3 h,the reaction was poured into aq. ammonia (30 mL) and thenfiltered—washing with dichloromethane. The filtrate was extracted withdichloromethane (50 mL×3). The combined extracts were dried, filtered,concentrated, and purified by reverse-phase HPLC to give8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-1-(2-(dimethylamino)ethyl)-7-methoxyquinolin-2(1H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (s, 1H), 8.73 (s, 2H), 7.91 (d, 1H),7.12 (d, 1H), 4.94 (s, 1H), 4.71 (t, 2H), 4.58 (m, 1H), 3.90 (s, 3H),2.22 (m, 2H), 2.04 (s, 6H), 1.80-1.50 (m, 8H); MS (ESI): 491.0.

EXAMPLE 116-(4-(3,5-Dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoicacid

Step 1

Concentrated HCl (15 ml) was added to a solution of8-(cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(1.2 g, 2.90 mmol, Example 3) and methanol (8 ml). The reaction mixturewas heated at 50° C. for 4 h and then concentrated. The residue wasneutralized with sat'd NaHCO₃, filtered (washed with ethanol and ether),and dried to give4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one:MS (ESI): 352.

Step 2

Sodium hydride (54 mg, 1.35 mmol) was added to a solution of4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one(380 mg, 1.08 mmol) and DMSO (20 ml) at rt under N₂. After 1 h, ethyl6-bromohexanoate (770 mg, 3.45 mmol) was added, and the mixture washeated at 30° C. for 5 h. The reaction was quenched with drops of water,poured into 0.5 M KH₂PO₄, and extracted with EtOAc (100 mL×3). Thecombined extracts were washed with water and then brine, dried,filtered, concentrated, and purified by silica gel chromatography (ethylacetate: pet. ether) to give ethyl6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoate:MS (ESI): 494.0.

Step 3

Lithium hydroxide (2.0 mL, 1M, 2.0 mmol) was added to a solution ofethyl6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoate(100 mg, 0.20 mmol), MeOH (2 mL), and THF (8 mL). The mixture wasstirred for 24 h, quenched with 1N HCl (30 mL), and extracted with EtOAc(40 mL×2). The organic extracts were dried, filtered, and concentratedto give6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoicacid: ¹H NMR (400 MHz, DMSO-d₆): δ 10.10 (s, 1H), 8.88 (s, 1H), 8.77 (s,2H), 7.89 (d, 1H), 7.06 (d, 1H), 4.80 (s, 1H), 3.95 (t, 2H), 3.90 (s,3H), 2.22 (t, 2H), 1.76 (m, 2H), 1.55 (m, 2H), 1.39 (m, 2H); MS (ESI):465.8.

EXAMPLE 124-(3,5-Dimethylpyridin-4-ylamino)-8-isobutoxy-7-methoxyquinolin-2(1H)-one

The title compound was prepared from methyl3-hydroxy-4-methoxy-2-nitrobenzoate (Example 1, Step 1) and1-bromo-2-methylpropane following the procedures outlined in Examples 1& 8. ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.42 (s, 1H), 8.39 (s,2H), 7.89 (d, 1H), 7.03 (d, 1H), 4.51 (s, 1H), 3.89 (s, 3H), 3.74 (d,2H), 2.13 (s, 6H), 2.13 (m, 1H), 0.97 (d, 6H); MS (ESI): 368.2.

EXAMPLE 134-(3,5-Dichloropyridin-4-ylamino)-8-(4-(dimethylamino)butoxy)-7-methoxyquinolin-2(1H)-one

Step 1

8-(4-Bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-onewas prepared from4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one(Example 11, Step 1) and 1,4-dibromobutane following the procedureoutlined in Example 11, Step 2. MS (ESI): 485.8.

Step 2

A solution of dimethylamine (1.5 mL, 2M THF, 3 mmol) was added to asolution of8-(4-bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(146 mg, 0.3 mmol) and DMSO (3 mL). After 2.5 h, the reaction was pouredinto 10% K₂CO₃ (30 mL) and extracted with dichloromethane (40 mL×2). Thecombined extracts were dried, filtered, concentrated, and purified bysilical gel chromatography (1:0→4:1; dichlormethane:methanol w/1% conc.NH₄OH solution) and then reverse-phase HPLC (1:9→1:1;acetonitrile:water) to give4-(3,5-dichloropyridin-4-ylamino)-8-(4-(dimethylamino)butoxy)-7-methoxyquinolin-2(1H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 10.29 (s, 1H), 8.81 (s, 1H), 8.75 (s, 2H),7.87 (d, 1H), 7.04 (d, 1H), 4.77 (s, 1H), 3.99 (t, 2H), 3.90 (s, 3H),2.27 (t, 2H), 2.13 (s, 6H), 1.73 (m, 2H), 1.54 (m, 2H); MS (ESI): 451.0.

EXAMPLE 144-(3,5-Dichloropyridin-4-ylamino)-8-(5-(dimethylamino)pentyloxy)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one(Example 11, Step 1) and 1,5-dibromopentane following the proceduresoutlined in Example 13. ¹H NMR (400 MHz, DMSO-d₆): δ 9.91 (s, 1H), 8.83(s, 1H), 8.75 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.77 (s, 1H), 3.96(t, 2H), 3.90 (s, 3H), 2.19 (t, 2H), 2.10 (s, 6H), 1.76 (m, 2H),1.48-1.32 (m, 4H) MS (ESI): 465.0.

The following compounds can generally be made using the methodsdescribed above. It is expected that these compounds when made will haveactivity similar to those that have been made in the examples above.

The following compounds are represented herein using the SimplifiedMolecular Input Line Entry System, or SMILES. SMILES is a modernchemical notation system, developed by David Weininger and DaylightChemical Information Systems, Inc., that is built into all majorcommercial chemical structure drawing software packages. Software is notneeded to interpret SMILES text strings, and an explanation of how totranslate SMILES into structures can be found in Weininger, D., J. Chem.Inf. Comput. Sci. 1988, 28, 31-36. All SMILES strings used herein weregenerated using Accelrys's Pipeline Pilot 6.0. Many IUPAC names usedherein were generated using CambridgeSoft's ChemDraw 10.0.

O═C1C═C(NC2=C(C)C═NC═C2C)C3=C(N1)C(OCCCCN(C)C)═C(OC)C═C3O═C1C═C(NC2=C(C)C═NC═C2C)C3=C(N1)C(OCCCCCN(C)C)═C(OC)C═C3O═C1C═C(NC2=C(C)C═NC═C2C)C3=C(N1)C(OCCCCC(O)═O)═C(OC)C═C3O═C1C═C(NC2=C(C)C═NC═C2C)C3=C(N1)C(OCCCCN4CCN(C)CC4)=C(OC)C═C3O═C1C═C(NC2=C(C)C═NC═C2C)C3=C(N1)C(OCCCCN4CCOCC4)=C(OC)C═C3O═C1C═C(NC2=C(C)C═NC═C2C)C3=C(N1)C(OCCCCCC(O)═O)═C(OC)C═C3═OC1C═C(NC2=C(C)C═NC═C2C)C3=C(N1)C(OCC(N)═O)═C(OC)C═C3O═C1C═C(NC2=C(C)C═NC═C2C)C3=C(N1)C(OCCCCC(N)═O)═C(OC)C═C3O═C1C═C(NC2=C(C)C═NC═C2C)C3=C(N1)C(OCCCCCCC(O)═O)═C(OC)C═C3COc1ccc2C(═CC(═O)Nc2c1OCCCCN)Nc3c(C)cncc3CCNCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3CCOc1ccc2C(═CC(═O)Nc2c1OCCCCCN)Nc3c(C)cncc3CCc1cncc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N)c(OCF)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N)Nc3c(C)cncc3CCOc1ccc2C(═CC(═O)Nc2c1OCCCCN)Nc3c(C)cncc3FCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cncc3FCc1cncc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N)c(OCF)ccc23COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cncc3ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCN)Nc3c(F)cncc3FCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(F)cncc3FNC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3FCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(F)cncc3ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCN)Nc3c(C)cccc3CCc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCN)c(OCF)ccc23CNCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3CCOc1ccc2C(═CC(═O)Nc2c1OCCCCCN)Nc3c(C)cccc3CCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cccc3CCc1cccc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N)c(OCF)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N)Nc3c(C)cccc3CCOc1ccc2C(═CC(═O)Nc2c1OCCCCN)Nc3c(C)cccc3FCNCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3FCOc1ccc2C(═CC(═O)Nc2c1OCCCCCN)Nc3c(C)cccc3FCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cccc3FCc1cccc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N)c(OCF)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N)Nc3c(C)cccc3FCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cccc3ClCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cc(F)cc3CCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cc(F)cc3FCOc1ccc2C(═CC(═O)Nc2c1OCCCCN)Nc3c(C)cc(O)cc3CCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cc(O)cc3CCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cc(O)cc3FCOc1ccc2C(═CC(═O)Nc2c1OCCCCN)Nc3c(F)cccc3FCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(F)cccc3FNC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3FCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(F)cccc3ClCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(F)cc(F)cc3FCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(F)cc(O)cc3FCN(C)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3CCCCN(C)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3CCc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCn4cccn4)c(OC(F)(F)F)ccc23COCCOCCOCCOCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3CCc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCCN)c(OC(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCCn3 ccnc3)Nc4c(C)cccc4CCc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCCCNC(═N)N)c(OC(F)(F)F)ccc23Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCCCC4)c(OC(F)F)ccc23Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCCCn4 ccnn4)c(OCF)ccc23CC(C)[C@H](NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3C)C(═O)OCc1cccc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](Cc4 ccccc4)C(═O)O)c(OC(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](CCSC)C(═O)O)Nc3c(C)cccc3CCc1cccc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N[C @@H](CCCNC(═N)N)C(═O)O)c(OC(F)(F)F)ccc23Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCC(═O)NCC(═O)O)c(OC(F)(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](CCCCN)C(═O)O)Nc3c(C)cccc3CCc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C @@H](CCCCN)C(═O)O)c(OCF) ccc23Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](Cc4cnc[nH]4)C(═O)O)c(OC(F)F)ccc23CN1CCN(CC1)C(═O)CCCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(C)cccc4CCc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](Cc4ccc(O)cc4)C(═O)O)c(OCF)ccc23Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](Cc4ccc(O)cc4)C(═O)O)c(OC(F)F)ccc23CCNCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3FCCN(C)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3FCOCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3FCOc1ccc2C(═CC(═O)Nc2c1OCCCCCNC(═N)N)Nc3c(C)cccc3FCc1cccc(F)c1NC2=CC(═O)Nc3c(OCCCCCn4cnnc4)c(OC(F)F)ccc23Cc1cccc(F)c1NC2=CC(═O)Nc3c(OCCCCCOc4 ccncc4)c(OCF)ccc23CCNCCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3FCc1cccc(F)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCCC(F)C4)c(OCF)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCCCOc3 cccnc3)Nc4c(C)cccc4FCc1cccc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N)c(OC(F)(F)F)ccc23CN(C)CCOC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3FCc1cccc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CO)C(═O)O)c(OC(F)F)ccc23Cc1cccc(F)c1NC2=CC(═O)Nc3c(OCCCC(═O)N[C@@H](Cc4c[nH]c5 ccccc45)C(═O)O)c(OCF)ccc23Cc1cccc(F)c1NC2=CC(═O)Nc3c(OCCCC(═O)N[C@@H](Cc4c[nH]c5 ccccc45)C(═O)O)c(OC(F)F)ccc23Cc1cccc(F)c1NC2=CC(═O)Nc3c(OCCCCC(═O)OCC[N+](C)(C)C)c(OC(F)(F)F)ccc23CC(C)[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3F)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](CCCCN)C(═O)O)Nc3c(C)ccc c3FCc1cccc(F)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N)c(OCF)ccc23CN1CCN(CC1)C(═O)CCCCCOc2c(OC(F)F)ccc3C(═CC(═O)Nc23)Nc4c(C)cccc4FCC[C@H](C)[C@H](NC(═O)CCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3F)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCOCC3)Nc4c(C)cccc4ClCc1cccc(Cl)c1NC2=CC(═O)Nc3c(OCCCCN4CCC(F)CC4)c(OC(F)F)ccc23Cc1cccc(Cl)c1NC2=CC(═O)Nc3c(OCCCCOc4ccccn4)c(OC(F)(F)F)ccc23Cc1cccc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCNC(═N)N)c(OCF)ccc23CCCCCN(C)CCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3ClCc1cccc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCOc4 cccnc4)c(OC(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCCCN)Nc3c(C)cccc3ClCc1cccc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCOCC4)c(OC(F)(F)F)ccc23COCCOCCOCCCCCCOc1c2NC(═O)C═C(Nc3c(C)cccc3Cl)c2 ccc1OC(F)FCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](C(C)C)C(═O)O)Nc3c(C)cccc3ClCC(C)C[C@H](NC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3Cl)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](Cc3c[nH]c4 ccccc34)C(═O)O)Nc5c(C)cccc5ClCc1cccc(Cl)c1NC2=CC(═O)Nc3c(OCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)c(OCF)ccc23CC(C)[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3Cl)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)Nc3c(C)cccc3ClCC(C)C[C@H](NC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3Cl)C (═O)OCc1cccc(Br)c1NC2=CC(═O)Nc3c(OCCCCN)c(OC(F)F)ccc23COCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3BrCOc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCC(F)C3)Nc4c(C)cccc4BrCc1cccc(Br)c1NC2=CC(═O)Nc3c(OCCCCCN4CCCC(F)C4)c(OC(F)F)ccc23Cc1cccc(Br)c1NC2=CC(═O)Nc3c(OCCCCCn4cccc4)c(OC(F)(F)F)ccc23CCCNCCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3BrCOc1ccc2C(═CC(═O)Nc2c1OCCCCCCn3cnnn3)Nc4c(C)cccc4BrCOCCOCCOCCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3BrCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](CO)C(═O)O)Nc3c(C)cccc3BrCc1cccc(Br)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CCCCN)C(═O)O)c(OC(F)F) ccc23Cc1cccc(Br)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CCC(═O)O)C(═O)O)c(OCF) ccc23CN(C)CCN(C)C(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3BrCN1CCN(CC1)C(═O)CCCOc2c(OC(F)F)ccc3C(═CC(═O)Nc23)Nc4c(C)cccc4BrCOc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](CO)C(═O)O)Nc3c(C)cccc3BrCN(C)CCCN(C)C(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3BrCN(CCC[N+](C)(C)C)C(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3BrCN(CCC[N+](C)(C)C)C(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3BrCOc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](Cc3 ccc(O)cc3)C(═O)O)Nc4c(C)cccc4BrCCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3CCOc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCCCC3)Nc4c(C)cc(F)cc4CCc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCN4CCCC4)c(OCF)ccc23CCCCCN(C)CCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3CCc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCn4nccn4)c(OC(F)F)ccc23Cc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCOc4 ccncc4)c(OC(F)(F)F)ccc23Cc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCCn4 ccnc4)c(OC(F)F)ccc23Cc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCC(═O)OCC[N+](C)(C)C)c(OCF)ccc23CN(C)CCCN(C)C(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3CCc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCC(═O)OCC[N+](C)(C)C)c(OC(F)(F)F)ccc23Cc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N4CCC [C@H]4C(═O)O)c(OCF)c cc23COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N(C)CCN(C)C)Nc3c(C)cc(F)cc3CCc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N4CCC[C@H]4C(═O)O)c(OC(F)(F)F)ccc23Cc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](Cc4 ccccc4)C(═O)O)c(OCF)ccc23Cc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCn4cnnn4)c(OC(F)F)ccc23Cc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCOc4 ccncc4)c(OC(F)(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCO[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)Nc4c(C)cc(F)cc4FCCCCN(C)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3FCc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCCOc4 ccncc4)c(OCF)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCCCN)Nc3c(C)cc(F)cc3FCOCCN(C)CCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3FCc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCCCC4)c(OCF)ccc23Cc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCCCn4nccn4)c(OC(F)F)ccc23CC(C)C[C@H](NC(═O)COc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3F)C(═O)OCC(C)[C@H](NC(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3F)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](CCCCN)C(═O)O)Nc3c(C)cc(F) cc3FCN(C)CCN(C)C(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3FCOc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N3CCNCC3)Nc4c(C)cc(F)cc4FCc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](Cc4ccc(O)cc4)C(═O)O)c(OCF)ccc23Cc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CCC(═O)N)C(═O)O)c(OC(F)(F)F)ccc23CC(C)[C@H](NC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3F)C(═O)OCc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](Cc4 ccccc4)C(═O)O)c(OCF)ccc23CCCCN(C)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCn3 ccnc3)Nc4c(C)cc(F)cc4ClCc1cc(F)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCOc4 cccnc4)c(OC(F)(F)F)ccc23COCCN(C)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3ClCc1cc(F)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCn4ncnn4)c(OC(F)(F)F)ccc23Cc1ccc2C(═CC(═O)Nc2c1OCCCCCOc3 cccnc3)Nc4c(C)cc(F)cc4ClCc1cc(F)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCOc4 ccncc4)c(OC(F)F)ccc23CCCCN(C)CCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3ClCc1cc(F)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCC(F)C4)c(OCF)ccc23Cc1cc(F)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCCn4cccc4)c(OC(F)F)ccc23Cc1cc(F)cc(Cl)c1NC2=CC(═O)Nc3c(OCC(═O)NCC(═O)O)c(OC(F)(F)F)ccc23Cc1cc(F)cc(Cl)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CO)C(═O)O)c(OCF)ccc23CN(CCC[N+](C)(C)C)C(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3 ClCOc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](CCCCN)C(═O)O)Nc3c(C)cc(F) cc3ClCc1cc(F)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCC(═O)N[C@@H](CCCCN)C(═O)O)c(OC(F)F)ccc23Cc1cc(F)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CO)C(═O)O)c(OCF) ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H]([C@@H](CO)C(═O)O)Nc3c(C)cc(F)cc3ClCc1cc(F)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CCCCN)C(═O)O)c(OC(F)(F)F)ccc23Cc1cc(F)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)c(OC(F)F)ccc23Cc1cc(F)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)OCC [N+](C)(C)C)c(OCF)ccc23Cc1cc(F)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](CO)C(═O)O)c(OC(F)(F)F)ccc23COCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3BrCc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCn4 ccnn4)c(OC(F)F)ccc23CCCCCN(C)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3BrCOc1ccc2C(═CC(═O)Nc2c1OCCCCCN3CCC(F)CC3)Nc4c(C)cc(F)cc4BrCOCCOCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3BrCc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCCC(F)(F)C4)c(OC(F)(F)F)ccc 23Cc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCn4 ccnc4)c(OC(F)F)ccc23Cc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CCC(═O)O)C(═O)O)c(OC(F)(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](CCC(═O)N)C(═O)O)Nc3c(C)cc(F)cc3BrCc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCC(═O)OCC[N+](C)(C)C)c(OCF)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](CCCCN)C(═O)O)Nc3c(C)cc(F)cc3BrCc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CCCCN)C(═O)O)c(OC(F)F)ccc23Cc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CCCCN)C(═O)O)c(OC(F)(F)F)ccc23Cc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)OCC[N+](C)(C)C)c(OCF)ccc23Cc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](CO)C(═O)O)c(OC(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)Nc3c(C)cc(F)cc3BrCCCNCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3CCc1cc(O)cc(C)c1NC2=CC(═O)Nc3c(OCCCCN4CCC(F)(F)C4)c(OCF)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCn3cnnc3)Nc4c(C)cc(O)cc4CCCCNCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3CCc1cc(O)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCn4cncn4)c(OC(F)(F)F)ccc23Cc1cc(O)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCn4cnnn4)c(OC(F)F)ccc23Cc1cc(O)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCOc4 ccncc4)c(OCF)ccc23COCCN(C)CCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3CCc1cc(O)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCOCC4)c(OC(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCCCN3CCCCC3)Nc4c(C)cc(O)cc4CCc1cc(O)cc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CC(═O)O)C(═O)O)c(OCF) ccc23COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](CC(═O)N)C(═O)O)Nc3c(C)cc(O)c c3CCN(C)CCCN(C)C(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3CCN(CCC[N+](C)(C)C)C(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3CC[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](Cc3 ccccc3)C(═O)O)Nc4c(C)cc(O)cc4CCc1cc(O)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](CO)C(═O)O)c(OC(F)(F)F)ccc23Cc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCCCCn4 cccn4)c(OCF)ccc23COCCOCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3FCCCN(C)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3FCc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCCCCCn4 ccon4)c(OC(F)F)ccc23Cc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCCCCCn4ncnn4)c(OC(F)(F)F)ccc23CNCCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3FCOCCOCCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3FCc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N)c(OC(F)(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](CC(C)C)C(═O)O)Nc3c(C)cc(O)cc3FCc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CO)C(═O)O)c(OCF)ccc23Cc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCCCC(═O)N4CCNCC4)c(OC(F)F)ccc23CN1CCN(CC1)C(═O)CCCOc2c(OCF)ccc3C(═CC(═O)Nc23)Nc4c(C)cc(O)cc4FCc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)c(OC(F)(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N3CCNCC3)Nc4c(C)cc(O)cc4FCC(C)[C@H](NC(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3F)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)NCC [N+](C)(C)C)Nc3c(C)cc(O)cc3FCc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](Cc4ccc(O)cc4)C(═O)O)c(OC(F)F)ccc23CCN(CC)CCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3ClCc1cc(O)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCN4CCCCC4)c(OC(F)(F)F)ccc23Cc1cc(O)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCN4CCC(F)C4)c(OC(F)F)ccc23CCNCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3ClCCCN(C)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCCn3cnnc3)Nc4c(C)cc(O)cc4ClCc1cc(O)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCOCCOCCOCCO)c(OC(F)(F)F)ccc23CCN(CC)CCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3ClCc1cc(O)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCCn4 ccnc4)c(OCF)ccc23Cc1cc(O)cc(Cl)c1NC2=CC(═O)Nc3c(OCC(═O)OCC [N+](C)(C)C)c(OC(F)F)ccc23Cc1cc(O)cc(Cl)c1NC2=CC(═O)Nc3c(OCC(═O)N4CCC [C@H]4C(═O)O)c(OCF)ccc23C[C@H](NC(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C1)C(═O)OC[C@@H](O)[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3Cl)C(═O)OCN(CCC[N+](C)(C)C)C(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C1Cc1cc(O)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N4CCNCC4)c(OC(F)F)ccc23Cc1cc(O)cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](CO)C(═O)O)c(OC(F)(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](CC(═O)N)C(═O)O)Nc3c(C)cc(O)cc3ClCc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCn4nccn4)c(OC(F)(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCOCCOCCOCCO)Nc3c(C)cc(O)cc3BrCc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCn4cnnc4)c(OC(F)F)ccc23Cc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCOc4ccccn4)c(OC(F)(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCCOc3 ccncc3)Nc4c(C)cc(O)cc4BrCCN(C)CCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3BrCc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCn4ncnn4)c(OCF)ccc23Cc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCOCCOCCOCCO)c(OC(F)(F)F)ccc23CC[C@H](C)[C@H](NC(═O)COc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3Br)C(═O)OCc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](Cc4ccc(O)cc4)C(═O)O)c(OCF)ccc23Cc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)c(OC(F)(F)F)ccc23Cc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCCCC(═O)N4CCC[C@H]4C(═O)O)c(OC(F)F)ccc23CN(C)CCN(C)C(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3BrCOc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](CC(═O)O)C(═O)O)Nc3c(C)cc(O)cc3BrCc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)c(OCF)ccc23Cc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCCn4cncn4)c(OC(F)F)ccc23)C(═O)OCc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCCn4cnnc4)c(OC(F)(F)F)ccc23)C(═O)OCc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCCOCCO)c(OCF)ccc23)C(═O)OCOCCOCCOCCOCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C)C(═O)OCc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCCCn4 ccon4)c(OC(F)F)ccc23)C(═O)OCc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCCCn4ncnn4)c(OCF)ccc23)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCCOc3 ccncc3)Nc4c(C)cc(cc4C)C(═O)OCc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCOCC4)c(OC(F)F)ccc23)C(═O)OCc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCCCCOCCO)c(OC(F)(F)F)ccc23)C(═O)OCN(C)CCNC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N(C)CCCN(C)C)Nc3c(C)cc(cc3C)C(═O)OCc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N4CCNCC4)c(OC(F)F)ccc23)C(═O)OCc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CO)C(═O)O)c(OC(F)(F)F)ccc23)C(═O)OCc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)c(OC(F)F)ccc23)C(═O)OC[C@@H](O)[C@H](NC(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C)C(═O)O)C(═O)OCN(C)CCOC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C)C(═O)OCN(C)CCNC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C)C(═O)OCc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCCCCN4CCCC(F)(F)C4)c(OCF)ccc23)C(═O)OCc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCCCCOc4ccccn4)c(OC(F)F)ccc23)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCCOc3 cconc3)Nc4c(C)cc(cc4F)C(═O)OCc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCCCCCOc4 ccncc4)c(OC(F)F)ccc23)C(═O)OCCCNCCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3F)C(═O)OCc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCCCCCCn4cnnc4)c(OC(F)(F)F)ccc23)C(═O)OCc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCCCCCCOc4ccccn4)c(OCF)ccc23)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCCCOc3 ccncc3)Nc4c(C)cc(cc4F)C(═O)OCc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N)c(OC(F)F)ccc23)C(═O)OCc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](Cc4ccc(O)cc4)C(═O)O)c(OCF)ccc23)C(═O)OCN(CC[N+](C)(C)C)C(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3F)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](CC(C)C)C(═O)O)Nc3c(C)cc(cc3F)C(═O)OCc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N4CCC[C@H]4C(═O)O)c(OC(F)(F)F)ccc23)C(═O)OCN(CC[N+](C)(C)C)C(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3F)C(═O)OCN(CC[N+](C)(C)C)C(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3F)C(═O)OCC[C@H](C)[C@H](NC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3F)C(═O)O)C(═O)OCCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3Cl)C(═O)OCCCCCN(C)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3Cl)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCCC3)Nc4c(C)cc(cc4Cl)C(═O)OCc1cc(cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCn4cnnc4)c(OCF)ccc23)C(═O)OCc1cc(cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCn4cccc4)c(OCF)ccc23)C(═O)OCc1cc(cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCn4cncn4)c(OC(F)(F)F)ccc23)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCCn3cnnn3)Nc4c(C)cc(cc4C1)C(═O)OCN(C)CCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C1)C(═O)OCCN(C)CCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3Cl)C(═O)OCOCCOCCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3Cl)C(═O)OCc1cc(cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCCOCCOCCOCCO)c(OC(F)F)ccc23)C(═O)OCN(CC[N+](C)(C)C)C(═O)COc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3Cl)C(═O)OCc1cc(cc(Cl)c1NC2=CC(═O)Nc3c(OCCCC(═O)N4CCNCC4)c(OC(F)F)ccc23)C(═O) OCc1cc(cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCC(═O)NCC(═O)O)c(OC(F)F)ccc23)C(═O) OCc1cc(cc(Cl)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](Cc4ccccc4)C(═O)O)c(OCF)ccc23)C(═O)OCSCC[C@H](NC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3Cl)C(═O)O)C(═O)OCN1CCN(CC1)C(═O)CCCCCOc2c(OCF)ccc3C(═CC(═O)Nc23)Nc4c(C)cc(cc4C1)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](CO)C(═O)O)Nc3c(C)cc(cc3Cl)C(═O)OCN(C)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3Br)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCCN3CCOCC3)Nc4c(C)cc(cc4Br)C(═O)OCc1cc(cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCOCCOCCO)c(OCF)ccc23)C(═O)OCc1cc(cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCN)c(OC(F)F)ccc23)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCCCN3CCCC3)Nc4c(C)cc(cc4Br)C(═O)OCc1cc(cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCn4cnnn4)c(OC(F)(F)F)ccc23)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](Cc3c[nH]c4 ccccc34)C(═O)O)Nc5c(C)cc(cc5Br)C(═O)OCc1cc(cc(Br)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](Cc4c[nH]c5 ccccc45)C(═O)O)c(OCF)ccc23)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N3CCN(C)CC3)Nc4c(C)cc(cc4Br)C(═O) OCc1cc(cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N)c(OC(F)F)ccc23)C(═O)OCPc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)NCC(═O)O)Nc3c(C)cc(cc3Br)C(═O)OC[C@H](NC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3Br)C(═O)O)C(═O)OCc1cc(cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](CO)C(═O)O)c(OC(F)(F)F)ccc23)C(═O)OCCN(CC)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3FNC(═N)NCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3FCOc1ccc2C(═CC(═O)Nc2c1OCCCCOCCOCCOCCO)Nc3c(F)cccc3FFCOc1ccc2C(═CC(═O)Nc2c1OCCCCCN3CCOCC3)Nc4c(F)cccc4FFC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCn3 ccnn3)Nc4c(F)cccc4FCOCCOCCOCCCCCOc1c2NC(═O)C═C(Nc3c(F)cccc3F)c2 ccc1OC(F)(F)FFC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCCn3 ccnc3)Nc4c(F)cccc4FCOCCOCCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3FNCCCC[C@H](NC(═O)COc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F)C(═O)ONC(═N)NCCC[C@H](NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F)C(═O)ONC(═O)CC[C@H](NC(═O)COc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F)C(═O)ONC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3FCOc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N3CCNCC3)Nc4c(F)cccc4FNC(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3FC[N+](C)(C)CCNC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3FC[N+](C)(C)CCNC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3FCOc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N(C)CC[N+](C)(C)C)Nc3c(F)cccc3FNCCCC[C@H](NC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](Cc3cnc[nH]3)C(═O)O)Nc4c(F)cccc4FNCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3ClFc1cccc(Cl)c1NC2=CC(═O)Nc3c(OCCCCn4ncon4)c(OC(F)(F)F)ccc23COCCOCCOCCOCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3C1COc1ccc2C(═CC(═O)Nc2c1OCCCCCN(C)C)Nc3c(F)cccc3C1Fc1cccc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCN4CCCC(F)(F)C4)c(OC(F)(F)F)ccc23FCOc1ccc2C(═CC(═O)Nc2c1OCCCCCOc3 ccccn3)Nc4c(F)cccc4ClOCCOCCOCCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3ClCN(CCC[N+](C)(C)C)C(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3ClCN1CCN(CC1)C(═O)COc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(F)cccc4ClCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](CCCCN)C(═O)O)Nc3c(F)cccc3ClCOc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](C)C(═O)O)Nc3c(F)cccc3ClOC(═O)[C@H](Cc1ccc(O)cc1)NC(═O)CCCOc2c(OCF)ccc3C(═CC(═O)Nc23)Nc4c(F)cccc4ClC[C@@H](O)[C@H](NC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3Cl)C(═O)OCN(CC[N+](C)(C)C)C(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3ClOC(═O)CNC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3ClC[C@@H](O)[C@H](NC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3Cl)C(═O)OOC(═O)[C@H](Cc1cnc[nH]1)NC(═O)CCCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(F)cccc4ClNC(═O)C[C@H](NC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3Cl)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCOc3 cccnc3)Nc4c(F)cccc4BrFC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCN3CCC(F)CC3)Nc4c(F)cccc4BrFCOc1ccc2C(═CC(═O)Nc2c1OCCCCCOc3 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c1OC(═O)c1cc(Br)c(NC2=CC(═O)Nc3c(OCCCCCN4CCCC(F)(F)C4)c(OCF)ccc23)c(B r)c1OC(═O)c1cc(Br)c(NC2=CC(═O)Nc3c(OCCCCCn4cnnn4)c(OC(F)F)ccc23)c(Br)c1COCCOCCOCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cc(cc3Br)C(═O)OCNCCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cc(cc3Br)C(═O)OCOCCN(C)CCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cc(cc3Br)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCCCN3CCCC(F)(F)C3)Nc4c(Br)cc(cc4Br)C(═O) OOCCOCCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Br)cc(cc3Br)C(═O)OCN(C)CCNC(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Br)cc(cc3Br)C(═O)OC(═O)c1cc(Br)c(NC2=CC(═O)Nc3c(OCCCC(═O)N4CCNCC4)c(OC(F)F)ccc23)c(B 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cccnc4)c(OC(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCCCN(C)C)Nc3c(C)cncc3CCCNCCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3CCCN(C)CCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3CCCCCN(C)CCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3CC[C@H](NC(═O)COc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C)C(═O)OCc1cncc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N4CCC[C@H]4C(═O)O)c(OC(F)(F)F)cc c23COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](Cc3 ccccc3)C(═O)O)Nc4c(C)cncc4CC[C@@H](O)[C@H](NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C)C(═O)OCc1cncc(C)c1NC2=CC(═O)Nc3c(OCCCC(═O)OCC[N+](C)(C)C)c(OC(F)F)ccc23CN(CC[N+](C)(C)C)C(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc 3CCN(C)CCCN(C)C(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3CCOc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N3CCN(C)CC3)Nc4c(C)cncc4CCc1cncc(C)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N)c(OC(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N3CCNCC3)Nc4c(C)cncc4CCc1cncc(C)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CO)C(═O)O)c(OCF)ccc 23C[C@@H](O)[C@H](NC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C)C(═O)OCc1cncc(C)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N4CCNCC4)c(OCF)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)NCC(═O)O)Nc3c(C)cncc3CCc1cncc(C)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N4CCC[C@H]4C(═O)O)c(OC(F)F) ccc23CSCC[C@H](NC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C)C(═O)OCc1cncc(F)c1NC2=CC(═O)Nc3c(OCCCCN4CCCCC4)c(OC(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCC(F)(F)CC3)Nc4c(C)cncc4FCOCCOCCOCCOCCCCOc1c2NC(═O)C═C(Nc3c(C)cncc3F)c2 ccc1OCFCOCCOCCOCCOCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3FCN(C)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3FCc1cncc(F)c1NC2=CC(═O)Nc3c(OCCCCCN4CCC(F)(F)CC4)c(OCF)ccc23Cc1cncc(F)c1NC2=CC(═O)Nc3c(OCCCCCn4 cccn4)c(OC(F)(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCCOCCO)Nc3c(C)cncc3FCNCCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3FCCN(CC)CCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3FCc1ccc(F)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCCCC4)c(OC(F)(F)F)ccc23COCCOCCOCCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3FCc1cncc(F)c1NC2=CC(═O)Nc3c(OCC(═O)OCC[N+](C)(C)C)c(OCF)ccc23CN1CCN(CC1)C(═O)COc2c(OC(F)F)ccc3C(═CC(═O)Nc23)Nc4c(C)cncc4FCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](C(C)C)C(═O)O)Nc3c(C)cncc3FCc1cncc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](Cc4c[nH]c5 ccccc45)C(═O)O)c(OC(F)(F)F)ccc23Cc1cncc(F)c1NC2=CC(═O)Nc3c(OCCCC(═O)NCC 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(═O)OCN(C)CCCN(C)C(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3ClCN(CCC[N+](C)(C)C)C(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3 ClCOc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](C(C)C)C(═O)O)Nc3c(C)cncc3ClCc1cncc(Cl)c1NC2=CC(═O)Nc3c(OCCCC(═O)N[C@@H](CCC(═O)N)C(═O)O)c(OCF)ccc23CN(C)CCNC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)NCC[N+](C)(C)C)Nc3c(C)cncc3ClCc1cncc(Cl)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)c(OCF)ccc23Cc1cncc(Cl)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C @@H](CC(═O)O)C(═O)O)c(OC(F)F)ccc23CN(C)CCOC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3ClCc1ncc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)NCC(═O)O)c(OCF)ccc23C[C@H](NC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3Cl)C(═O)OCc1cncc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](Cc4c[nH]c5 ccccc45)C(═O)O)c(OCF)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](Cc3cnc[nH]3)C(═O)O)Nc4c(C)cncc4ClCc1cncc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H] (Cc4cnc[nH]4)C(═O)O)c(OC(F)F)ccc23Cc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCN4CCCC(F)C4)c(OC(F)(F)F)ccc23Cc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCN4CCCC(F)(F)C4)c(OC(F)F)ccc23Cc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCN4CCC(F)(F)C4)c(OCF)ccc23Cc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCOc4 ccncc4)c(OCF)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCOCCO)Nc3c(C)cncc3BrCN(C)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3BrCCN(CC)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3BrCCCCCN(C)CCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3BrCc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCCN4CCOCC4)c(OC(F)(F)F)ccc23COCCOCCOCCOCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3BrCc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCC(F)CC4)c(OCF)ccc23Cc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCCC(F)(F)C4)c(OC(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCCCn3 ccnn3)Nc4c(C)cncc4BrCc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCOc4 ccncc4)c(OC(F)F)ccc23COCCOCCOCCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3BrCN(C)CCOC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3BrCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N(C)CC[N+](C)(C)C)Nc3c(C)cncc3BrCc1cncc(Br)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H] (Cc4c[nH]c5 ccccc45)C(═O)O)c(OC(F)(F)F)ccc23Cc1cncc(Br)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H] (CC(═O)O)C(═O)O)c(OC(F)F)ccc23CC[C@H](C)[C@H](NC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3Br)C(═O)OCC[C@H](C)[C@H](NC(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3Br)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N3CCC[C@H]3C(═O)O)Nc4c(C)cncc4BrCc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCC(═O)N[C@@H] (CCCNC(═N)N)C(═O)O)c(OCF)ccc23CC(C)[C@H](NC(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3Br)C(═O)OC[C@@H](O)[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3Br)C(═O)OC[C@@H](O)[C@H](NC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3Br)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](Cc3cnc[nH]3)C(═O)O)Nc4c(C)cncc4BrCN(C)CCNC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3BrCN(CCC[N+](C)(C)C)C(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3BrCc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N4CCNCC4)c(OCF)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N3CCC [C@H]3C(═O)O)Nc4c(C)cncc4 BrFCOc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCCCC3)Nc4c(F)cncc4FFC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCCC(F)C3)Nc4c(F)cncc4FFC1 CCN(CCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(F)cncc4F)ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCn3nccn3)Nc4c(F)cncc4FCCCNCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3FCCN(C)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3FCOCCN(C)CCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3FFCOc1ccc2C(═CC(═O)Nc2c1OCCCCCn3cnnc3)Nc4c(F)cncc4FCOCCN(C)CCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3FFCOc1ccc2C(═CC(═O)Nc2c1OCCCCCCN3CCC(F)CC3)Nc4c(F)cncc4FFc1cncc(F)c1NC2=CC(═O)Nc3c(OCCCCCCn4ncnn4)c(OC(F)(F)F)ccc23FC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCCOc3 ccccn3)Nc4c(F)cncc4FCOCCOCCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3FC[N+](C)(C)CCNC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3FCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N(C)CCC[N+](C)(C)C)Nc3c(F)cncc3FCC(C)C[C@H](NC(═O)COc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3F)C(═O)OOC(═O)[C@H](Cc1c[nH]c2ccccc12)NC(═O)COc3c(OCF)ccc4C(═CC(═O)Nc34)Nc5c(F)cncc5FOC(═O)[C@H](Cc1cnc[nH]1)NC(═O)COc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(F)cncc4FNC(═O)CC[C@H](NC(═O)COc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3F)C(═O)OCC(C)[C@H](NC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3F)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N3CCC[C@H]3C(═O)O)Nc4c(F)cncc4FOC(═O)[C@H] (Cc1c[nH]c2 ccccc12)NC(═O)CCCOc3c(OCF)ccc4C(═CC(═O)Nc34)Nc5c(F)cncc5FOC(═O)[C@H](Cc1cnc[nH]1)NC(═O)CCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(F)cncc4FNC(═O)CC[C@H](NC(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3F)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)NCCN(C)C)Nc3c(F)cncc3FCC[C@H](C)[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3F)C(═O)OCSCC[C@H](NC(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3F)C(═O) OCSCC[C@H](NC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3F)C(═O)ONC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3FCN(C)CCN(C)C(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3FCOc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N(C)CCCN(C)C)Nc3c(F)cncc3FNCCCC[C@H](NC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3F)C(═O)OCCCCN(C)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3ClCCCCCN(C)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3ClFC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCn3cnnn3)Nc4c(F)cncc4ClCOCCOCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3ClOCCOCCOCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCCN(C)C)Nc3c(F)cncc3ClCN(C)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3ClCCN(C)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3ClCCN(C)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3ClNC(═N)NCCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCCCn3 cccc3)Nc4c(F)cncc4ClFc1cncc(Cl)c1NC2=CC(═O)Nc3c(OCCCCCCOc4 cconc4)c(OC(F)(F)F)ccc23COCCOCCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3ClC[C@H](NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Cl)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](CC(C)C)C(═O)O)Nc3c(F)cncc3ClNCCCC[C@H](NC(═O)COc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Cl)C(═O)ONC(═N)NCCC[C@H](NC(═O)COc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Cl)C(O)ONC(═N)NCCC[C@H](NC(═O)COc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3C1)C(═O)OCN(C)CCN(C)C(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3ClCOc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](C)C(═O)O)Nc3c(F)cncc3ClOC(═O)[C@@H]1CCCN1C(═O)CCCOc2c(OCF)ccc3C(═CC(═O)Nc23)Nc4c(F)cncc 4ClNC(═O)C[C@H](NC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Cl)C(═O)OOC(═O)[C@@H]1CCCN1C(═O)CCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(F)cncc4ClC(═O)[C@H](Cc1ccccc1)NC(═O)CCCCOc2c(OC(F)F)ccc3C(═CC(═O)Nc23)Nc4c(F)cncc4ClC(═O)[C@H](Cc1cnc[nH]1)NC(═O)CCCCOc2c(OCF)ccc3C(═CC(═O)Nc23)Nc4c(F)cncc4ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](CC(═O)N)C(═O)O)Nc3c(F)cncc3ClNC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](CC(C)C)C(═O)O)Nc3c(F)cncc3ClOC(═O)[C@H](Cc1c[nH]c2ccccc12)NC(═O)CCCCCOc3c(OC(F)(F)F)ccc4C(═CC(═O)Nc34)Nc5c(F)cncc5ClC(═O)C[C@H](NC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Cl)C(═O)OFc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCN4CCCCC4)c(OC(F)(F)F)ccc23COc1ccc2C(═CC(═O)Nc2c1OCCCCn3nccn3)Nc4c(F)cncc4BrCOCCOCCOCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3BrOCCOCCOCCOCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3BrCOc1ccc2C(═CC(═O)Nc2c1OCCCCCN(C)C)Nc3c(F)cncc3BrFc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCCN4CCCC4)c(OC(F)(F)F)ccc23FCOc1ccc2C(═CC(═O)Nc2c1OCCCCCN3CCC(F)(F)C3)Nc4c(F)cncc4BrFC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCOc3 ccncc3)Nc4c(F)cncc4BrOCCOCCOCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3BrNCCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3BrCOc1ccc2C(═CC(═O)Nc2c1OCCCCCCNC(═N)N)Nc3c(F)cncc3BrFc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCCCC4)c(OC(F)(F)F)ccc23FCOc1ccc2C(═CC(═O)Nc2c1OCCCCCCOc3 ccncc3)Nc4c(F)cncc4BrCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)NCC[N+](C)(C)C)Nc3c(F)cncc3BrCC(C)C[C@H](NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O)OCC[C@H](C)[C@H](NC(═O)COc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O)OOC(═O)[C@H](Cc1ccccc1)NC(═O)COc2c(OC(F)F)ccc3C(═CC(═O)Nc23)Nc4c(F)cncc4BrNCCCC[C@H](NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O)OCN(CC[N+](C)(C)C)C(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3BrCC(C)[C@H](NC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)Nc3c(F) cncc3BrNC(═O)C[C@H](NC(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N(C)CCC[N+](C)(C)C)Nc3c(F)cncc3BrC[C@H](NC(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O)OC[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O) OCC(C)C[C@H](NC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O)OC[N+](C)(C)CCOC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3BrCN(C)CCNC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3BrCOc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)NCC[N+](C)(C)C)Nc3c(F)cncc3BrC[N+](C)(C)CCNC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc 3BrCN(C)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCOCCO)Nc3c(Cl)cncc3ClOCCOCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3ClOCCOCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCCN)Nc3c(Cl)cncc3ClFC(F)(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCN3CCCC(F)(F)C3)Nc4c(Cl)cncc4ClFC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCN3CCC(F)C3)Nc4c(Cl)cncc4ClFCOc1ccc2C(═CC(═O)Nc2c1OCCCCCn3nccn3)Nc4c(Cl)cncc4ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCCn3cnnc3)Nc4c(Cl)cncc4ClFC1CCN(CCCCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(Cl)cncc4Cl)CClFC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCCN3CCC(F)(F)CC3)Nc4c(Cl)cncc4ClOCCOCCOCCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCCCOCCOCCOCCO)Nc3c(Cl)cncc3ClCN(C)CCOC(═O)COc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3ClC[N+](C)(C)CCNC(═O)COc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3ClFCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N3CCNCC3)Nc4c(Cl)cncc4ClCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](Cc3c[nH]c4 ccccc34)C(═O)O)Nc5c(Cl)cncc5 ClC(═O)[C@H](Cc1c[nH]c2 ccccc12)NC(═O)COc3c(OC(F)F)ccc4C(═CC(═O)Nc34)Nc5c(Cl)cncc5ClOC(═O)[C@H](Cc1c[nH]c2 ccccc12)NC(═O)CCCOc3c(OCF)ccc4C(═CC(═O)Nc34)Nc5c(Cl)cncc5ClOC[C@H](NC(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3Cl)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H]([C@@H](C)O)C(═O)O)Nc3c(Cl)cncc3ClOC(═O)C[C@H](NC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3Cl)C(═O)OC(═O)CNC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3ClNCCCC[C@H](NC(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3Cl)C(═O)OC(═O)CC [C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3Cl)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](CCC(═O)N)C(═O)O)Nc3c(Cl) cncc3ClNC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)OCCN(C)C)Nc3c(Cl)cncc3ClC[C@@H](O)[C@H](NC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3Cl)C(═O)ONC(═O)C[C@H](NC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3Cl)C(═O)OCCCCN(C)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3BrFC1CCN(CCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(Cl)cncc4Br)ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCn3 cccc3)Nc4c(Cl)cncc4BrFCOc1ccc2C(═CC(═O)Nc2c1OCCCCn3 ccnc3)Nc4c(Cl)cncc4BrFC1CCN(CCCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(Cl)cncc4Br)ClCOc1ccc2C(═CC(═O)Nc2c1OCCCCCn3cnnc3)Nc4c(Cl)cncc4BrFCOc1ccc2C(═CC(═O)Nc2c1OCCCCCn3ncnn3)Nc4c(Cl)cncc4BrCOCCOCCOCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3BrNCCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3BrCOCCN(C)CCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3BrFC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCCN3CCCCC3)Nc4c(Cl)cncc4BrCOCCOCCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3BrNC(═O)COc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3BrCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)OCC[N+](C)(C)C)Nc3c(Cl)cncc3BrCC(C)[C@H](NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3Br)C(═O)OOC(═O)[C@H](Cc1ccc(O)cc1)NC(═O)COc2c(OC(F)F)ccc3C(═CC(═O)Nc23)Nc4c(Cl)cncc4BrCOc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](C)C(═O)O)Nc3c(Cl)cncc3BrOC(═O)[C@H](Cc1ccc(O)cc1)NC(═O)CCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(Cl)cncc4BrOC(═O)C[C@H](NC(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3Br)C(═O)OOC(═O)CC[C@H](NC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3Br)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)OCC[N+](C)(C)C)Nc3c(Cl)cncc3BrCN(C)CCCN(C)C(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3BrCSCC[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3Br)C(═O)OOC[C@H](NC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3Br)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](Cc3 ccc(O)cc3)C(═O)O)Nc4c(C1)cncc4BrCSCC[C@H](NC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3Br)C(═O)OC(═O)C[C@H](NC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3Br)C(═O)ONC(═O)CC[C@H](NC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Cl)cncc3Br)C(═O)ONC(═N)NCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3BrFC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCC(F)CC3)Nc4c(Br)cncc4BrFCOc1ccc2C(═CC(═O)Nc2c1OCCCCn3 ccnn3)Nc4c(Br)cncc4BrCOCCOCCOCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3BrCCCNCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3BrCCCCN(C)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3BrFC1CCN(CCCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(Br)cncc4Br)C1FCOc1ccc2C(═CC(═O)Nc2c1OCCCCCn3 ccnn3)Nc4c(Br)cncc4BrCCCCN(C)CCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3BrFC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCCN3CCCCC3)Nc4c(Br)cncc4BrFC(F)(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCCn3 cccc3)Nc4c(Br)cncc4BrFCOc1ccc2C(═CC(═O)Nc2c1OCCCCCCn3ncnn3)Nc4c(Br)cncc4BrOC(═O)CNC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3BrCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](C)C(═O)O)Nc3c(Br)cncc3BrOC(═O)[C@H](Cc1ccccc1)NC(═O)COc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(Br)cncc4BrOC(═O)[C@H](Cc1ccc(O)cc1)NC(═O)COc2c(OC(F)F)ccc3C(═CC(═O)Nc23)Nc4c(Br)cncc4BrCOc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)NCCN(C)C)Nc3c(Br)cncc3BrCN(C)CCCN(C)C(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3BrOC(═O)[C@H](Cc1ccc(O)cc1)NC(═O)CCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(Br)cncc4BrOC[C@H](NC(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br)C(═O)OOC[C@H](NC(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N(C)CC[N+](C)(C)C)Nc3c(Br)cncc3BrCC(C)C[C@H](NC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br)C(═O)OOC(═O)[C@@H]1CCCN1C(═O)CCCCOc2c(OCF)ccc3C(═CC(═O)Nc23)Nc4c(Br)cncc4BrC[C@@H](O)[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br)C(═O)OCN(C)CCN(C)C(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3BrC[C@H](NC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br)C(═O)OCC(C)[C@H](NC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br)C(═O)OCOc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](Cc3 ccccc3)C(═O)O)Nc4c(Br)cncc4BrNC(═O)CC[C@H](NC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br)C(═O)O

The activity of the compounds in Examples 1-14 as PDE4 inhibitors isillustrated in the following assay. The other compounds listed above,which have not yet been made and/or tested, are predicted to haveactivity in this assay as well.

Novel PDE/AK Biological Activity Assay Protocol

Phosphodiesterases regulate the activity of the second messenger cyclicadenosine monophosphate (cAMP) by hydrolyzing cAMP to adenosinemonophosphate (AMP). We developed a novel coupled PDE/AK bioluminescenthigh-throughput assay to measure the activity of phosphodiesterases. Inthe PDE/AK assay, the AMP produced from the hydrolysis of cAMP byphosphodiesterase is converted to adenosine diphosphate (ADP) by thephosphotransferase activity of adenylate kinase (also known as ADK ormyokinase). Adenylate kinase will catalyze the conversion of 1 mole ofAMP and 1 mole of ATP into 2 moles of ADP. Thus the conversion of AMP toADP will result in the subsequent loss of ATP. The decrease in ATPconcentration can be monitored as light output using luciferase in areaction that requires ATP to produce light. The PDE/AK assay usesluciferase, which catalyzes the production of light from ATP present inthe reaction mix. The amount of emitted light is inversely proportionalto the level of AMP present in the reaction. Test compounds areincubated with the phosphodiesterases and phosphodiesterase inhibitorswill decrease the rate of cAMP hydrolysis and decrease the subsequentproduction of AMP. Thus phosphodiesterase inhibitors will decrease theconversion of ATP to ADP and result in the greatest emission of light.

Compounds may be screened for functional potency in in vitro biochemicalassays for their ability to inhibit the activity of phosphodiesterase(PDE) enzymes. A novel coupled PDE/AK assay was utilized to measure theinhibitory activity of compounds on PDE isoforms. The catalytic domainof PDE4B was fused to an amino-terminus hex-histidine affinity tag andpurified. PDE4B enzyme was incubated with compounds for 10 minutes.Cyclic AMP substrate, ATP and adenylate kinase were then added to thePDE enzyme mix and incubated for 45 minutes at room temperature. Acommercial ATP detection assay, Perkin Elmer's easyLite ATP detectionreagent, was then added to measure the relative amount of ATP present inthe reaction. After 10 minute incubation, the luminescent signal wasquantitated with either the Perkin Elmer Viewlux or Molecular DevicesAcquest or Analyst. Roflumilast and Rolipram are the positive controlsused in the assay.

The PDE/AK assay can be performed with any cAMP dependentphosphodiesterase, and can be performed in 96-, 384-, or 1536-wellplates. Unlike other phosphodiesterase activity assays, the PDE/AK assaydoes not require radioactive substrates, modified substrates, beads, orantibodies, which each have disadvantages. Specifically, the use ofradioactive substrates in a phosphodiesterase activity assay requiresspecial protocols for handling and waste disposal, and reducedthroughput. Modified substrates add the additional complexity ofpotentially altering the binding to the phosphodiesterase catalyticsite. Fluorescently modified substrates may cause fluorescence artifactsthat may interfere in the interpretation of assay results. The use ofbeads that selectively bind to either the cAMP or AMP may cause anadditional complexity in reagent handling. The use of antibodies thatselectively bind to either cAMP or AMP can be extremely costly with arelatively small signal to noise ratio. Therefore, the novel PDE/AKassay represents a simple, cost-effective alternative to known methods.

Additionally, the PDE/AK assay's mechanism offers advantages which makeit useful for comparison to other phosphodiesterase activity assays. Inconventional assays in which cAMP concentration is inverselyproportional to the output of bioluminescence (such as CambrexBiosciences's PDELight), phosphodiesterase catalyzes the hydrolysis ofcAMP to AMP that is subsequently converted to ATP, consumed by aluciferase enzyme, and results in an increased bioluminescent output. Aphosphodiesterase inhibitor prevents the hydrolysis of cAMP to AMP andconsequently results in a decreased bioluminescent output. However,compounds which exhibit luciferase inhibition activity would score as afalse positive for PDE inhibition in the conventional assay. Incontrast, the novel PDK/AK assay would not score luciferase inhibitorsas false positive for PDE inhibition because inhibition of PDE activitywould result in increased bioluminescence. However, compounds that arecapable of inhibiting both PDE and luciferase would be false negatives.Compounds that inhibit adenylate kinase would score as false positivesin the novel PDE/AK assay. Use of both types of assay, and comparison ofthe data from both, would yield a richer and more reliable data set.

Accordingly, contemplated herein is a method for the detection andquantitation of PDE inhibition which uses adenylate kinase coupled to anATP-depleting assay.

In certain embodiments, said method comprises the steps of:

-   -   1. A first incubation, of PDE, or an isolated isoform thereof,        with a compound to be tested;    -   2. Addition of ATP, cAMP, and AK substrates;    -   3. A second incubation of said PDE;    -   4. Coupling to a means for readout of ATP-depletion; and    -   5. Readout.

In further embodiments, said first incubation is for between about 5 andabout 15 minutes; in yet further embodiments, said first incubation isfor about 10 minutes.

In further embodiments, said second incubation is for longer than about30 minutes; in yet further embodiments, said sufficient length of timeis between about 30 minutes and about one hour; in even furtherembodiments, sufficient length of time is about 45 minutes.

In further embodiments, said readout means is a luciferase assay. In yetfurther embodiments, said luciferase assay is a Perkin Elmer easyLiteassay.

In further embodiments, said readout is done on a machine for detectinga luminescent signal. In yet further embodiments, said machine isselected from the group consisting of a Perkin Elmer Viewlux, aMolecular Devices Acquest, and a Molecular Devices Analyst.

Results are shown below in Table 1.

TABLE 1 Biological Activity IC₅₀ Example + indicates ≦1 μM No. −indicates >1 μM 1 + 2 + 3 + 4 + 5 + 6 + 7 + 8 + 9 + 10 + 11 + 12 + 13 +14 +

In Vivo Assay Lacrimal Gland Inflammation-Induced Dry Eye in Rabbits

A more detailed description of the assay used herein may be found inNaglehout, T J et al. 2005, “Preservation of Tear Film Integrity andInhibition of Corneal Injury by Dexamethasone in a Rabbit Model ofLacrimal Gland Inflammation-Induced Dry Eye,” J. Ocular Pharm. Ther.,21:2. 139-148, the disclosure of which is hereby incorporated byreference as if written herein in its entirety.

Initiation of Dry Eye and Treatment

Rabbits (n=4/group) were randomized into treatment groups and dosedtopically BID with maxidex vehicle or test drug beginning one day priorto initiation of dry eye. Each rabbit received bilateral lacrimal glandinjections of saline or ConA (300 μg/30 μl) and topical ocular dosingwas continued BID throughout the study.

Corneal Staining

Desiccation was initiated 1-2 hours following lacrimal gland injectionby placing conscious rabbits in the environmental chamber (10-15%humidity/72° F.). Following 72 consecutive hours of exposure to this dryenvironment, the animals were anesthetized and sutures were placed ineach upper and lower eyelid and lifted to form a corneal/conjunctivalcup. Methylene blue dye (1 mL, 1% in dH₂O) was added to the cup forthree minutes and the excess removed by washing with 200 mL BSS®. Thecontralateral eye was then stained using the same procedure. Rabbitswere euthanized immediately following the staining procedure and theeyes were excised. The corneas were isolated with a trephine and the9.5-mm punch of the cornea was placed in 2 mL acetone/saturated sodiumsulfate (7:3, vol./vol.). Absorbance of the extracted dye was determinedat 660 nm.

Tear Breakup Time (TBUT)

TBUT was quantified in a separate group of treated animals. TBUT wasdetermined by instilling 5 μL sodium fluorescein into the cul de sac andmanually blinking the lids to distribute the fluorescein within the tearfilm. Under slit lamp observation, the eye was held open and the timewhereby one or more black spots or streaks appeared in the precornealtear film was recorded. The rabbits were euthanized 3 days followingConA injection.

Data reported as NT refers to the example having been not tested.

TABLE 2 In Vivo Activity Example Activity at Percent ConcentrationTested No. 1 × 10⁻⁶ 1 × 10⁻⁵ 1 × 10⁻⁴ 1 × 10⁻³ 1 × 10⁻² 1 × 10⁻¹ 1 1 NTNT NT NT Inactive Inactive Inactive 5 Inactive NT Inactive NT InactiveNT NT 8 Inactive NT Inactive NT Inactive NT NT

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A method of inhibition of PDE4 comprisingcontacting PDE4 with a compound of structural Formula IV

or a salt, ester, or prodrug thereof, wherein: X³ is (CR¹⁸R¹⁹); R¹ andR² are independently selected from the group consisting of—(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy,alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl,alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted; s is 1-8; G¹is selected from the group consisting of alkoxy, amino, amido, carbonyl,hydroxy, ether, an amino acid, and null; G² is selected from the groupconsisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl,heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, an aminoacid, and null, any of which may be optionally substituted; G³ isselected from the group consisting of alkyl, alkoxy, amino, hydroxy,ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted; R³and R⁴ are each independently selected from the group consisting ofhydrogen, halogen, alkoxy and lower alkyl; R⁵ is selected from the groupconsisting of —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)— and —(CR¹²R¹³)_(p)—; W isselected from the group consisting of O, N(R⁷), C(O)N(R⁷), and SO_(q);m, n, and q are independently 0, 1 or 2; p is 1 or 2; R⁶ is selectedfrom the group consisting of carboxyl, alkylcarboxy, amido, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, acyl, andhydroxamic acid, any of which may be optionally substituted; R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from the groupconsisting of hydrogen and optionally substituted lower alkyl; R¹⁴ isselected from the group consisting of hydrogen, halogen, hydroxyl, loweralkyl, hydroxyalkyl, aminoalkyl, and haloalkyl; and R¹⁸ and R¹⁹ are eachindependently selected from the group consisting of hydrogen, halogen,lower alkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl,aminoalkoxy and a bond.
 2. A method of treatment of a PDE4-mediateddisease comprising the administration to a patient in need thereof of atherapeutically effective amount of a compound of Formula IV

or a salt, ester, or prodrug thereof, wherein: X³ is (CR¹⁸R¹⁹); R¹ andR² are independently selected from the group consisting of—(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy,alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl,alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted; s is 1-8; G¹is selected from the group consisting of alkoxy, amino, amido, carbonyl,hydroxy, ether, an amino acid, and null; G² is selected from the groupconsisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl,heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, an aminoacid, and null, any of which may be optionally substituted; G³ isselected from the group consisting of alkyl, alkoxy, amino, hydroxy,ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted; R³and R⁴ are each independently selected from the group consisting ofhydrogen, halogen, alkoxy and lower alkyl; R⁵ is selected from the groupconsisting of —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)— and —(CR¹²R¹³)_(p)—; W isselected from the group consisting of O, N(R⁷), C(O)N(R⁷), and SO_(q);m, n, and q are independently 0, 1 or 2; p is 1 or 2; R⁶ is selectedfrom the group consisting of carboxyl, alkylcarboxy, amido, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, acyl, andhydroxamic acid, any of which may be optionally substituted; R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from the groupconsisting of hydrogen and optionally substituted lower alkyl; R¹⁴ isselected from the group consisting of hydrogen, halogen, hydroxyl, loweralkyl, hydroxyalkyl, aminoalkyl, and haloalkyl; and R¹⁸ and R¹⁹ are eachindependently selected from the group consisting of hydrogen, halogen,lower alkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl,aminoalkoxy and a bond.
 3. (canceled)
 4. (canceled)
 5. (canceled)
 6. Amethod of treatment of a PDE4-mediated disease comprising theadministration of: a. a therapeutically effective amount of a compoundof structural Formula IV

or a salt, ester, or prodrug thereof, wherein: X³ is (CR¹⁸R¹⁹); R¹ andR² are independently selected from the group consisting of—(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy,alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl,alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted; s is 1-8; G¹is selected from the group consisting of alkoxy, amino, amido, carbonyl,hydroxy, ether, an amino acid, and null; G² is selected from the groupconsisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl,heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, an aminoacid, and null, any of which may be optionally substituted; G³ isselected from the group consisting of alkyl, alkoxy, amino, hydroxy,ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted; R³and R⁴ are each independently selected from the group consisting ofhydrogen, halogen, alkoxy and lower alkyl; R⁵ is selected from the groupconsisting of —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)— and —(CR¹²R¹³)_(p)—; W isselected from the group consisting of O, N(R⁷), C(O)N(R⁷), and SO_(q);m, n, and q are independently 0, 1 or 2; p is 1 or 2; R⁶ is selectedfrom the group consisting of carboxyl, alkylcarboxy, amido, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, acyl, andhydroxamic acid, any of which may be optionally substituted; R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from the groupconsisting of hydrogen and optionally substituted lower alkyl; R¹⁴ isselected from the group consisting of hydrogen, halogen, hydroxyl, loweralkyl, hydroxyalkyl, aminoalkyl, and haloalkyl; and R¹⁸ and R¹⁹ are eachindependently selected from the group consisting of hydrogen, halogen,lower alkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl,aminoalkoxy and a bond; and b. another therapeutic agent.
 7. The methodas recited in claim 2, wherein the compound is of structural Formula V

or a salt, ester, or prodrug thereof, wherein: R¹ and R² areindependently selected from the group consisting of —(CH₂)_(s)G¹G²G³,acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl,amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl,carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl,guanidine, heteroaryl, heteroaralkyl, and hydroxyalkyl, any of which maybe optionally substituted; s is 1-8; G¹ is selected from the groupconsisting of alkoxy, amino, amido, carbonyl, hydroxy, ether, an aminoacid, and null; G² is selected from the group consisting of alkyl,alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl,carboxylalkylamino, guanidine, an amino acid, and null, any of which maybe optionally substituted; G³ is selected from the group consisting ofalkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, anamino acid, phosphonate, phosphoamide, and null, any of which may beoptionally substituted; R⁵ is selected from the group consisting of—(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)— and —(CR¹²R¹³)_(p)—; W is selected from thegroup consisting of O, N(R⁷), C(O)N(R⁷), and SO_(q); m, n, and q areindependently 0, 1 or 2; p is 1 or 2; R⁶ is selected from the groupconsisting of carboxyl, alkylcarboxy, amido, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, acyl, and hydroxamicacid, any of which may be optionally substituted; R⁷ and R¹⁴ areindependently selected from the group consisting of hydrogen, halogen,hydroxyl, lower alkyl, hydroxyalkyl, haloalkyl, and aminoalkyl; R⁸, R⁹,R¹⁰, R¹¹, R¹² and R¹³ are independently selected from the groupconsisting of hydrogen and optionally substituted lower alkyl; and R¹⁹is selected from the group consisting of hydrogen, halogen, lower alkyland haloalkyl.
 8. The method as recited in claim 7, wherein R⁷ and R¹⁴are independently selected from the group consisting of hydrogen,halogen and optionally substituted lower alkyl.
 9. The method as recitedin claim 8, wherein R⁶ is selected from the group consisting of aryl andheteroaryl, either of which may be optionally substituted;
 10. Themethod as recited in claim 9, wherein R¹⁹ is hydrogen.
 11. The method asrecited in claim 10, wherein R⁶ is selected from the group consisting ofphenyl, pyridine, pyrimidine, pyridazine, and pyrazine, any of which maybe optionally substituted.
 12. The method as recited in claim 11,wherein R¹⁴ is hydrogen.
 13. The method as recited in claim 12, wherein:R⁵ is —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)—; m and n are both 0; W is N(R⁷); andR⁷ is hydrogen.
 14. The method as recited in claim 13, wherein R² islower alkyl.
 15. The method as recited in claim 14, wherein: R¹ isselected from the group consisting of —(CH₂)_(s)G¹G²G³, lower alkyl,cycloalkyl, cycloalkylalkyl, and heterocycloalkyl, any of which may beoptionally substituted; s is 1-6; G¹ is selected from the groupconsisting of amino, amido, and null; G² is selected from the groupconsisting of alkoxy, aryl, halo, heterocycloalkyl, and null, any ofwhich may be optionally substituted; and G³ is selected from the groupconsisting of alkyl, carboxyl, and null, any of which may be optionallysubstituted.
 16. The method as recited in claim 15, wherein R² ismethyl.
 17. The method as recited in claim 16, wherein R⁶ has a formulaselected from the group consisting of

and R²⁰, R²¹, R²², R²³ and R²⁴ are independently selected from the groupconsisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy,lower haloalkyl, lower haloalkoxy, amino, and carboxyl.
 18. A method oftreatment of a PDE4-mediated disease comprising the administration to apatient in need thereof of a therapeutically effective amount of acompound of structural Formula VI

or a salt, ester, or prodrug thereof, wherein: R¹ and R² areindependently selected from the group consisting of —(CH₂)_(s)G¹G²G³,acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl,amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl,carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl,guanidine, heteroaryl, heteroaralkyl, and hydroxyalkyl, any of which maybe optionally substituted; s is 1-8; G¹ is selected from the groupconsisting of alkoxy, amino, amido, carbonyl, hydroxy, ether, an aminoacid, and null; G² is selected from the group consisting of alkyl,alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl,carboxylalkylamino, guanidine, an amino acid, and null, any of which maybe optionally substituted; G³ is selected from the group consisting ofalkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, anamino acid, phosphonate, phosphoamide, and null, any of which may beoptionally substituted; and R²⁰ and R²⁴ are independently selected fromthe group consisting of hydrogen, halogen, hydroxyl, lower alkyl, loweralkoxy, lower haloalkyl, lower haloalkoxy, amino, and carboxyl.
 19. Themethod as recited in claim 18, wherein R²⁰ and R²⁴ are independentlyselected from the group consisting of hydrogen, halogen, and loweralkyl.
 20. The method as recited in claim 19, wherein R² is lower alkyl.21. The method as recited in claim 20, wherein: R¹ is selected from thegroup consisting of —(CH₂)_(s)G¹G²G³, lower alkyl, cycloalkyl,cycloalkylalkyl, and heterocycloalkyl, any of which may be optionallysubstituted; s is 1-6; G¹ is selected from the group consisting ofamino, amido, and null; G² is selected from the group consisting ofalkoxy, aryl, halo, heterocycloalkyl, and null, any of which may beoptionally substituted; and G³ is selected from the group consisting ofalkyl, carboxyl, and null, any of which may be optionally substituted.22. The method as recited in claim 21, wherein R² is methyl.
 23. Amethod of treatment of a PDE4-mediated disease comprising theadministration to a patient in need thereof of a therapeuticallyeffective amount of a compound of structural Formula VII

or a salt, ester, or prodrug thereof, wherein: R¹ and R² areindependently selected from the group consisting of —(CH₂)_(s)G¹G²G³,acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl,amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl,carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl,guanidine, heteroaryl, heteroaralkyl, and hydroxyalkyl, any of which maybe optionally substituted; s is 1-8; G¹ is selected from the groupconsisting of alkoxy, amino, amido, carbonyl, hydroxy, ether, an aminoacid, and null; G² is selected from the group consisting of alkyl,alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl,carboxylalkylamino, guanidine, an amino acid, and null, any of which maybe optionally substituted; G³ is selected from the group consisting ofalkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, anamino acid, phosphonate, phosphoamide, and null, any of which may beoptionally substituted; and R²⁰, R²², and R²⁴ are independently selectedfrom the group consisting of hydrogen, halogen, hydroxyl, lower alkyl,lower alkoxy, lower haloalkyl, lower haloalkoxy, amino, and carboxyl.24. The method as recited in claim 23, wherein R²⁰, R²², and R²⁴ areindependently selected from the group consisting of hydrogen, halogen,and lower alkyl.
 25. The method as recited in claim 24, wherein R² islower alkyl.
 26. The method as recited in claim 25, wherein: R¹ isselected from the group consisting of —(CH₂)_(s)G¹G²G³, lower alkyl,cycloalkyl, cycloalkylalkyl, and heterocycloalkyl, any of which may beoptionally substituted; s is 1-6; G¹ is selected from the groupconsisting of amino, amido, and null; G² is selected from the groupconsisting of alkoxy, aryl, halo, heterocycloalkyl, and null, any ofwhich may be optionally substituted; and G³ is selected from the groupconsisting of alkyl, carboxyl, and null, any of which may be optionallysubstituted.
 27. The method as recited in claim 26, wherein R² ismethyl.
 28. The method as recited in claim 2, wherein the compound isselected from the group consisting of Examples 1 to
 14. 29. (canceled)30. (canceled)
 31. (canceled)
 32. (canceled)
 33. The method as recitedin claim 2, wherein the diseases is an allergic disease.
 34. The methodas recited in claim 33, wherein the disease is chosen from allergicrhinitis and chronic sinusitis.
 35. The method as recited in claim 7,wherein the diseases is an allergic disease.
 36. The method as recitedin claim 35, wherein the disease is chosen from allergic rhinitis andchronic sinusitis.
 37. The method as recited in claim 18, wherein thediseases is an allergic disease.
 38. The method as recited in claim 37,wherein the disease is chosen from allergic rhinitis and chronicsinusitis.
 39. The method as recited in claim 22, wherein the diseasesis an allergic disease.
 40. The method as recited in claim 39, whereinthe disease is chosen from allergic rhinitis and chronic sinusitis. 41.The method as recited in claim 23, wherein the diseases is an allergicdisease.
 42. The method as recited in claim 41, wherein the disease ischosen from allergic rhinitis and chronic sinusitis.